4-benzoyl isoxazoles derivatives and their use as herbicides

ABSTRACT

4-Benzoylisoxazole derivatives of formula (I), wherein R  
                 
 
     represents hydrogen or ester; R 1  represents alkyl, haloalkyl or optionally substituted cycloalkyl; R 2  represents halogen, optionally halogenated alkyl, alkenyl or alkynyl; alkyl substituted by one or more groups —OR 5 ; nitro, cyano, —CO 2 R 5 , —S(O) p R 6 , —O(CH 2 ) m OR 5 , —COR 5 , —NR 5 R 6 , —N(R 8 )SO q R 7 , —CONR 9 R 10  or —OR 51 ; optionally substituted phenyl; R 3  represents —S(O) q R 7 ; X represents —N(R 8 )—; n represents zero or an integer from one to four; R 5 , R 51  and R 6  independently represent hydrogen, optionally halogenated alkyl, alkenyl or alkynyl; optionally substituted phenyl; or cycloalkyl; R 7  represents alkyl, alkenyl or alkynyl optionally substituted by halogens; cycloalkyl; optionally substituted phenyl; or amino; R 8  represents hydrogen; alkyl, alkenyl or alkynyl optionally substituted by halogens; cycloalkyl; optionally substituted phenyl; or alkoxy; m is 1, 2 or 3; p is 0, 1 or 2; and q is zero or two; and their used as herbicides is described.

[0001] This invention relates to novel 4-benzoylisoxazole derivatives,compositions containing them, processes for their preparation,intermediates in their preparation and their use as herbicides.

[0002] Herbicidal 4-benzoylisoxazoles are described in European PatentPublication Number 0418175.

[0003] The present invention provides 4-benzoylisoxazole derivatives offormula (I):

[0004] wherein:

[0005] R represents the hydrogen atom or a group —CO₂R⁴;

[0006] R¹ represents:—

[0007] a straight- or branched- chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms; or

[0008] a cycloalkyl group containing from three to six carbon atomsoptionally substituted by one or more R⁵ groups or one or more halogenatoms;

[0009] R² represents:—

[0010] a halogen atom;

[0011] a straight- or branched- chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0012] a straight- or branched- chain alkyl group containing up to sixcarbon atoms which is substituted by one or more groups —OR⁵;

[0013] a group selected from nitro, cyano, —CO₂R⁵, —S(O)_(p)R⁶,—O(CH₂)_(m)OR⁵, —COR⁵, —NR⁵R⁶, —N(R⁸)SO_(q)R⁷, —CONR⁹R¹⁰ and —OR⁵¹;

[0014] phenyl optionally substituted by from one to three groups R²¹which may be the same or different;

[0015] R³ represents S(O)_(q)R⁷;

[0016] X represents a group —N(R⁸)—;

[0017] n represents zero or an integer from one to four; where n isgreater than one the groups R² may be the same or different;

[0018] R⁴ represents a straight- or branched- chain alkyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0019] R⁵, R⁵¹ and R⁶, which may be the same or different, eachrepresents:—

[0020] the hydrogen atom;

[0021] a straight- or branched-chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0022] phenyl optionally substituted by from one to five groups R² whichmay be the same or different; or

[0023] a cycloalkyl group containing from three to six carbon atoms;

[0024] R⁷ represents:—

[0025] a straight- or branched- chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0026] a cycloalkyl group containing from three to six carbon atoms;

[0027] phenyl or benzyl optionally substituted by from one to fivegroups R²¹ which may be the same or different;

[0028] or —NR⁹R¹⁰;

[0029] R⁸ represents:

[0030] the hydrogen atom;

[0031] a straight- or branched- chain alkyl alkenyl or alkynyl groupcontaining up to ten carbon atoms optionally substituted by-one or morehalogen atoms;

[0032] a cycloalkyl group containing from three to six carbon atoms;

[0033] phenyl optionally substituted by from one to five groups whichmay be the same or different selected from halogen, nitro, cyano, R⁵,S(O)_(p)R⁵ and —OR⁵; or

[0034] a group —OR¹¹;

[0035] R⁹ represents:—

[0036] the hydrogen atom;

[0037] a straight- or branched- chain alkyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms;

[0038] or phenyl optionally substituted by from one to five groups R²which may be the same or different;

[0039] R¹⁰ represents a group selected from R⁵ and —OR¹¹;

[0040] or R⁹ and R¹⁰, together with the nitrogen to which they areattached, may form a 5 or 6 membered ring optionally containing anoxygen or nitrogen atom in the ring (e.g. pyrrolidine, morpholine,pyrrole, piperidine and piperazine), wherein the ring is optionallysubstituted by one or more alkyl groups containing up to 3 carbon atoms;

[0041] R¹¹ represents a straight- or branched- chain alkyl groupcontaining up to six carbon atoms;

[0042] R²¹ represents:—

[0043] a halogen atom;

[0044] a straight- or branched- chain alkyl group containing up to threecarbon atoms optionally substituted by one or more halogen atoms;

[0045] or a group selected from nitro, cyano, —S(O)_(p)R⁵ and —OR⁵;

[0046] m represents one, two or three; and

[0047] p represents zero, one or two.

[0048] q represents zero or two;

[0049] and agriculturally acceptable salts thereof, which possessvaluable herbicidal properties.

[0050] Furthermore in certain cases the groups R, R¹, R², and R³ maygive rise to geometric and/or optical isomers. All such forms areembraced by the present invention

[0051] By the term “agriculturally acceptable salts” is meant salts thecations or anions of which are known and accepted in the art for theformation of salts for agricultural or horticultural use. Preferably thesalts are water-soluble.

[0052] The compounds of the invention, in some aspects of theiractivity, for example in their control of important weeds found incereal crops, e.g. Galium aparine and Avena fatua, and in theirselectivity in important cereal crops, e.g. wheat, show advantages overknown compounds.

[0053] It will be understood that in the above definition R² does notinclude substituents containing two or more phenyl rings linked througha bridging group.

[0054] In one embodiment the invention provides compounds of formula Iabove wherein:

[0055] R represents the hydrogen atom or a group —CO₂R⁴;

[0056] R¹ represents:—

[0057] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms; or

[0058] a cycloalkyl group containing from three to six carbon atomsoptionally substituted by one or more R⁵ groups;

[0059] R² represents:—

[0060] a straight- or branched-chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0061] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is substituted by a group —OR⁵;

[0062] a halogen atom;

[0063] phenyl optionally substituted by from one to three groups R²¹which may be the same or different;

[0064] a group selected from —COR⁵, nitro, cyano, —CO₂R⁵, —S(O) R⁶,—O(CH₂)_(m)OR⁵, —N(R⁸)SO₂R⁷, —CONR⁹R¹⁰ and —OR⁵¹;

[0065] R³ represents —S(O)_(q)R⁷;

[0066] X represents a group —N(R⁸)—;

[0067] n represents zero or an integer from one to four; where n isgreater than one the groups R² may be the same or different;

[0068] R⁴ represents a straight- or branched- chain alkyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0069] R⁵ represents:—

[0070] a straight- or branched- chain alkyl alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms; or

[0071] a cycloalkyl group containing from three to six carbon atoms;

[0072] R⁵¹ represents:—

[0073] a straight- or branched- chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0074] a cycloalkyl group containing from three to six carbon atoms;

[0075] or phenyl optionally substituted by from one to five groups whichmay be the same or different selected from a halogen atom, a straight-or branched- chain alkyl group containing up to three carbon atomsoptionally substituted by one or more halogen atoms; nitro, cyano,—S(O)_(p)R⁵ and —OR⁵;

[0076] R⁶ represents:—

[0077] a straight- or branched- chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0078] a cycloalkyl group containing from three to six carbon atoms;

[0079] or phenyl optionally substituted by from one to five groups whichmay be the same or different selected from a halogen atom, a straight-or branched-chain alkyl group containing up to three carbon atomsoptionally substituted by one or more halogen atoms; nitro, cyano,—S(O)_(p)R⁵ and —OR⁵;

[0080] R⁷ represents:—

[0081] a straight- or branched-chain alkyl alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0082] a cycloalkyl group containing from three to six carbon atoms;

[0083] phenyl optionally substituted by from one to five groups R²¹which may be the same or different;

[0084] or —NR⁹R¹⁰;

[0085] R⁸ represents:

[0086] the hydrogen atom; or

[0087] a straight- or branched-chain alkyl alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0088] a cycloalkyl group containing from three to six carbon atoms;

[0089] phenyl optionally substituted by from one to five groups whichmay be the same or different selected from a halogen atom, a straight-or branched-chain alkyl group containing up to three carbon atomsoptionally substituted by one or more halogen atoms; nitro, cyano,—S(O)_(p)R⁵ and —OR⁵;

[0090] or a group —OR¹¹;

[0091] R⁹ represents hydrogen or a straight- or branched-chain alkylgroup containing up to six carbon atoms optionally substituted by one ormore halogen atoms;

[0092] R¹⁰ represents a group selected from R⁵ and —OR¹¹;

[0093] or R⁹ and R¹⁰, together with the nitrogen to which they areattached, may form a S or 6 membered ring optionally containing anoxygen or nitrogen atom in the ring (e.g. pyrrolidine, morpholine,pyrrole, piperidine and piperazine), wherein the ring is optionallysubstituted by one or more alkyl groups containing up to 3 carbon atoms;

[0094] R¹¹ represents a straight- or branched-chain alkyl groupcontaining up to six carbon atoms;

[0095] R²¹ represents:—

[0096] a halogen atom;

[0097] a straight- or branched-chain alkyl group containing up to threecarbon atoms optionally substituted by one or more halogen atoms; or

[0098] a group selected from nitro, cyano, —S(O)_(p)R5 and —OR⁵;

[0099] m represents one, two or three; p represents zero, one or two;

[0100] and q represents two.

[0101] In a further embodiment the invention provides compounds offormula I above wherein:

[0102] R represents the hydrogen atom or a group —CO₂R⁴;

[0103] R¹ represents:—

[0104] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms; or

[0105] a cycloalkyl group containing from three to six carbon atomsoptionally substituted by one or more R⁵ groups or one or more halogenatoms;

[0106] R² represents:—

[0107] a halogen atom;

[0108] a straight- or branched-chain alkyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms;

[0109] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is substituted by one or more groups —OR⁵;

[0110] a group selected from nitro, cyano, —CO₂R⁵, —S(O)_(p)R⁶,—O(CH₂)_(m)OR⁵, —COR⁵, —NR⁵R⁶, —N(R⁸)SO_(q)R⁷ and —OR⁵¹;

[0111] R³ represents —S(O)_(q)R⁷;

[0112] X represents a group —N(R⁸)—;

[0113] n represents zero or an integer from one to four; where n isgreater than one the groups R² may be the same or different;

[0114] R⁴ represents a straight- or branched-chain alkyl groupcontaining up to six carbon atoms which is optionally substituted by oneor more halogen atoms;

[0115] R⁵, R⁵¹ and R⁶, which may be the same or different, eachrepresents:

[0116] the hydrogen atom;

[0117] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms;

[0118] phenyl optionally substituted by from one to five groups R² whichmay be the same or different;

[0119] R⁷ represents:

[0120] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms;

[0121] phenyl optionally substituted by from one to five groups R²¹which may be the same or different; or

[0122] a group —NR⁹R¹⁰;

[0123] R⁸ represents:

[0124] the hydrogen atom;

[0125] a straight- or branched-chain alkyl, alkenyl or alkynyl groupcontaining up to ten carbon atoms which is optionally substituted by oneor more halogen atoms; or

[0126] phenyl optionally substituted from one to five groups which maybe the same or different selected from nitro, halogen, R⁵ and —OR⁵;

[0127] R⁹ and R¹⁰, which may be the same or different, each represents:—

[0128] the hydrogen atom;

[0129] a straight- or branched-chain alkyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms;

[0130] or phenyl optionally substituted by from one to five groups R²which may be the same or different;

[0131] R²¹ represents:—

[0132] a halogen atom;

[0133] a straight- or branched-chain alkyl group containing up to threecarbon atoms optionally substituted by one or more halogen atoms;

[0134] or a group selected from nitro, cyano, —S(O)_(p)R⁶ and —OR⁵;

[0135] p represents zero, 1 or 2;

[0136] q represents zero or 2; and

[0137] m represents 1, 2 or 3.

[0138] Preferably the 5- and 6-positions of the benzoyl ring areunsubstituted.

[0139] Preferably the 2-position of the benzoyl ring is substituted.

[0140] A preferred class of compounds of formula (I) are those wherein:

[0141] R¹ represents:—

[0142] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is optionally substituted by one or more halogenatoms; or

[0143] a cycloalkyl group containing from three to six carbon atomsoptionally substituted by one or more methyl groups;

[0144] R² represents:—

[0145] a halogen atom;

[0146] a straight- or branched-chain alkyl, alkenyl or alkynyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

[0147] a straight- or branched-chain alkyl group containing up to sixcarbon atoms which is substituted by a group —OR⁵;

[0148] phenyl optionally substituted by from one to three groups R²¹which may be the same or different;

[0149] or a group selected from —COR⁵, cyano, nitro, —CO₂R⁵,—S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵, —N(R⁸)SO₂R⁷ and —OR⁵¹;

[0150] n represents zero or an integer from one to three; where a isgreater than one the groups R² may be the same or different;

[0151] R⁵ represents:—

[0152] a straight- or branched-chain alkyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms;

[0153] or a cycloalkyl group containing from three to six carbon atoms;

[0154] R⁵¹ and R⁶, which may be the same or different, each represents:—

[0155] a straight- or branched-chain alkyl or alkenyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

[0156] a straight- or branched-chain alkynyl group containing from threeto six carbon atoms;

[0157] a cycloalkyl group containing three to six carbon atoms;

[0158] R⁷ represents:—

[0159] a straight- or branched-chain alkyl or alkenyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

[0160] a straight- or branched-chain alkynyl group containing from threeto six carbon atoms;

[0161] a cycloalkyl group containing three to six carbon atoms; or

[0162] phenyl optionally substituted by from one to three groups R²¹which may be the same or different;

[0163] R⁸ represents:—

[0164] the hydrogen atom; or

[0165] a straight- or branched-chain alkyl or alkenyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

[0166] a straight- or branched-chain alkynyl group containing from threeto six carbon atoms;

[0167] or a cycloalkyl group containing three to six carbon atoms;

[0168] R²¹ represents:—

[0169] a halogen atom;

[0170] a straight- or branched-chain alkyl group containing up to threecarbon atoms optionally substituted by one or more halogen atoms; or

[0171] a group selected from nitro, cyano, —S(O)_(p)R⁵ and —OR⁵;

[0172] q represents two;

[0173] m represents two or three; and

[0174] p represents zero, one or two.

[0175] A further preferred class of compounds of formula (I) are thosewherein:—

[0176] R¹ represents:—

[0177] a straight- or branched-chain alkyl group containing up to threecarbon atoms; or

[0178] a cycloalkyl group containing three or four carbon atomsoptionally substituted by a methyl group;

[0179] R² represents:—

[0180] a chlorine, bromine or fluorine atom; or

[0181] a straight- or branched-chain alkyl alkenyl or alkynyl groupcontaining up to four carbon atoms optionally substituted by one or morehalogen atoms;

[0182] a straight- or branched-chain alkyl group containing up to fourcarbon atoms which is substituted by a group —OR⁵, or

[0183] a group selected from —COR⁵, —CO₂R⁵, —S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵,—N(R⁸)SO₂R⁷ and —OR⁵¹;

[0184] R⁵ and R⁶, which may be the same or different, each represents:—

[0185] a straight- or branched-chain alkyl group containing up to fourcarbon atoms optionally substituted by one or more chlorine, bromine orfluorine atoms; or

[0186] a cyclopropyl group;

[0187] R⁵¹ and R⁷, which may be the same or different, each represents:—

[0188] a straight- or branched-chain alkyl or alkenyl group containingup to four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms;

[0189] a straight- or branched-chain alkynyl group containing three orfour carbon atoms; or

[0190] a cyclopropyl group;

[0191] R⁸ represents:—

[0192] the hydrogen atom;

[0193] a straight- or branched-chain alkyl or alkenyl group containingup to four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms;

[0194] a straight- or branched-chain alkynyl group containing three orfour carbon atoms; or

[0195] a cyclopropyl group;

[0196] q represents two;

[0197] m represents two or three; and

[0198] p represents zero, one or two.

[0199] A further preferred class of compound are those wherein:—

[0200] R¹ represents:—

[0201] a methyl, ethyl, isopropyl, cyclopropyl or 1-methylcyclopropylgroup;

[0202] R² represents:—

[0203] a bromine, chlorine or fluorine atom; or

[0204] a straight- or branched-chain alkyl or alkenyl group containingup to four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms;

[0205] a group selected from —COR⁵, —CO₂R⁵, —SR⁶, —O(CH₂)_(m)OR⁵, —OR⁵¹and —N(R⁸)SO₂R⁷; or

[0206] a straight- or branched chain alkyl group containing up to fourcarbon atoms which is substituted by —OR⁵;

[0207] R⁵ and R⁶, which may be the same or different, each represents astraight- or branched-chain alkyl group containing up to three carbonatoms;

[0208] R⁵¹ represents:—

[0209] a straight- or branched-chain alkyl group containing up to fourcarbon atoms optionally substituted by one or more chlorine, bromine orfluorine atoms;

[0210] a straight- or branched-chain alkenyl or alkynyl group containingthree or four carbon atoms; or

[0211] a cyclopropyl group;

[0212] R⁷ represents:—

[0213] a straight- or branched-chain alkyl group containing up to threecarbon atoms optionally substituted by one or more chlorine, bromine, orfluorine atoms; or

[0214] an allyl group optionally substituted by one or more chlorine,fluorine or bromine atoms;

[0215] R⁸ represents:—

[0216] the hydrogen atom;

[0217] a straight- or branched-chain alkyl group containing up to threecarbon atoms optionally substituted by one or more chlorine, bromine, orfluorine atoms; or

[0218] an allyl group optionally substituted by one or more chlorine,fluorine or bromine atoms;

[0219] q represents two; and

[0220] m represents two or three.

[0221] A further preferred class of compounds of formula (I) are thosewherein:

[0222] R¹ represents cyclopropyl;

[0223] R² represents:

[0224] a halogen atom;

[0225] R⁷ represents methyl;

[0226] R⁸ represents hydrogen or methyl; and

[0227] n represents zero or one.

[0228] A further preferred class of compounds of formula (I) are thosewherein a group —XR³ is in the 2- or 4-position of the benzoyl ring.

[0229] A further preferred class of compounds of formula (I) are thosewherein:

[0230] R represents hydrogen or —CO₂Et;

[0231] R¹ represents cyclopropyl;

[0232] R² represents a halogen atom or a group selected from nitro,trifluoromethyl, methyl, trifluoromethoxy, —S(O)_(p)Me and —N(R⁸)SO₂R⁷;

[0233] R⁷ represents a straight- or branched-chain alkyl groupcontaining up to three carbon atoms, phenyl or benzyl;

[0234] R⁸ represents a straight- or branched-chain alkyl groupcontaining up to four carbon atoms, methoxy or phenyl;

[0235] p is zero, one or preferably two;

[0236] n represents zero, one or two; and

[0237] q represents two.

[0238] Particularly important compounds of formula (I) include thefollowing:

[0239] 1.4-[2-chloro4-(methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0240] 2.4-[4-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0241] 3.5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-benzoyl]isoxazole;

[0242] 4.4-[4-chloro-2-(N-ethyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0243] 5.5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-4-nitro-benzoylisoxazole;

[0244] 6. 5-cyclopropyl 4-[4-(N-methyl-N-methylsulphonyl)amino-2nitro-benzoyl]isoxazole;

[0245] 7.5-cyclopropyl4-[4-methyl-2-(N-methyl-N-methylsulphonyl)amino-benzoyl]isoxazole;

[0246] 8.4-[4-chloro-2-(N-n-propyl-N-methylsulphonyl)amninobenzoyl]-5-cyclopropylisoxazole;

[0247] 9. 5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonyl)amino4methylsulphonylbenzoyl]isoxazole;

[0248] 10.5-cyclopropyl-4-[3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoyl]isoxazole;

[0249] 11.5-cyclopropyl4q[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole;

[0250] 12. 5S-cyclopropyl42-(N-phenyl-N-methylsulphonyl)amino-benzoyl]isoxazole;

[0251] 13.[4-(4-bromo-2-(N-methyl-N-methylsulphonyl)amino-benzoyl]-5-cyclopropylisoxazole;

[0252] 14.5-cyclopropyl4-([2-(N-methyl-N-methylsulphonyl)amino-4-methylsulphonylbenzoyl]isoxazole;

[0253] 15. ethyl5-cyclopropyl-4-[4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoyl]isoxazole-3-carboxylate;

[0254] 16.4-[4chloro-2-(N-methyl-N-ethylsulphonylamino)benzoyl]-5-cyclopropyl-isoxazole;

[0255]17.5-cyclopropyl-4-[2,4-bis(N-methyl-N-methylsulphonyl)-aminobenzoyl]isoxazole;

[0256] 18.5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino4-fluorobenzoyl]isoxazole;

[0257] 19.4-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0258] 20.4-[2-chloro4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0259] 21.4-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenzoyl]-5-cyclopropylisoxazole;

[0260] 22. 5-cyclopropyl([2-(N-methyl-N-methylsulphonyl)amino4trifluoromethoxybenzoyl]isoxazole;

[0261] 23.4-[5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0262] 24.5-cyclopropyl4-[2-fluoro-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;

[0263] 25.5-cyclopropyl4-[3,4-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;

[0264] 26.5-cyclopropyl4-[4,5-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;

[0265] 27. 5-cyclopropyl4[4-iodo-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;

[0266] 28.4-[4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0267] 29.4-[4-chloro-2-(N-methyl-N-n-propylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0268] 30.4-([4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0269] 31.4-[4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0270] 32.4-[4-chloro-2-(N-methyl-N-isopropylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0271] 33.4-[4-chloro-2-(N-methoxy-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;

[0272] 34. ethyl5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole-3-carboxylate.

[0273] The numbers 1 to 34 are assigned to these compounds for referenceand identification hereinafter.

[0274] Compounds of formula (I) may be prepared by the application oradaptation of known methods (i.e. methods heretofore used or describedin the literature), for example as hereinafter described.

[0275] In the following description where symbols appearing in formulaeare not specifically defined, it is to be understood that they are “ashereinbefore defined” in accordance with the first definition of eachsymbol in the specification.

[0276] It is to be understood that in the descriptions of the followingprocesses the sequences may be performed in different orders, and thatsuitable protecting groups may be required to achieve the compoundssought.

[0277] According to a feature of the present invention compounds offormula (I) in which R represents hydrogen excluding those wherein agroup —XR³ is in the ortho position and X is —NH— may be prepared by thereaction of a compound of formula (II):

[0278] wherein L is a leaving group and R¹, R², R³, n and X are ashereinbefore defined provided that when X is —NH— the group —XR³ is notin the ortho position of the phenyl ring, with hydroxylamine or a saltof hydroxylamine. Hydroxylamine hydrochloride is generally preferred.Generally L is alkoxy, for example ethoxy, or N,N-dialkylamino, forexample dimethylamino. The reaction is generally carried out in anorganic solvent such as ethanol or acetonitrile or a mixture of awater-miscible organic solvent and water, preferably in a ratio oforganic solvent: water of from 1:99 to 99:1, optionally in the presenceof a base or acid acceptor such as triethylamine or sodium acetate at atemperature from room temperature to the boiling point of the solvent.

[0279] According to a further feature of the present invention compoundsof formula (I) in which R represents hydrogen may be prepared by thereaction of a compound of formula (III):

[0280] wherein R¹ is as hereinbefore defined and Y represents a carboxygroup or a reactive derivative thereof (such as a carboxylic acidchloride or carboxylic ester), or a cyano group, with an appropriateorganometallic reagent such as a Grignard reagent or an organolithiumreagent. The reaction is generally carried out in an inert solvent suchas ether or tetrahydrofuran at a temperature from 0° C. to the refluxtemperature of the mixture.

[0281] According to a further feature of the present invention compoundsof formula (I) wherein R represents a group —CO₂R⁴ excluding thosewherein a group —XR³ is in the ortho position-and X is —NH— may beprepared by the reaction of a compound of formula (IV)

[0282] wherein R¹, R², R³, X and n are as hereinbefore defined providedthat when X is —NH— the group —XR³ is not in the ortho position of thephenyl ring, and P is a leaving group such as N,N-diallylamino, with acompound of formula R⁴O₂CC(Z)=NOH wherein R⁴ is as hereinbefore definedand Z is a halogen atom. Generally Z is chlorine or bromine. Thereaction is generally performed in an inert solvent such as toluene ordichloromethane either in the presence of a base such as triethylamnineor a catalyst such as a 4 Angstrom molecular sieve or fluoride ion.

[0283] According to a further feature of the present invention compoundsof formula I in which R represents a group —CO₂R⁴ excluding thosewherein a group —XR³ is in the ortho position and X is —NH— may beprepared by the reaction of a compound of formula (V):

[0284] wherein R¹, R², R³, X and n are as hereinbefore defined providedthat when X is —NH— the group —XR³ is not in the ortho position of thephenyl ring, with a compound of formula R⁴O₂CC(Z)=NOH wherein Z and R⁴are as hereinbefore defined. The reaction is generally performed in aninert solvent such as toluene or dichloromethane optionally in thepresence of a base such as triethylamine or a catalyst such as a 4Angstrom molecular sieve or fluoride ion. The reaction can be carriedout at a temperature between room temperature and the reflux temperatureof the mixture.

[0285] According to a further feature of the present invention compoundsof formula (I) wherein R represents —CO₂R⁴ excluding those wherein agroup —XR³ is in the ortho position of the phenyl ring and X is —NH— maybe prepared by the reaction of a salt of compounds of formula (VI):

[0286] wherein R¹, R², R³, X and n are as hereinbefore defined providedthat when X is —NH— the group —XR³ is not in the ortho position of thephenyl ring, with a compound of formula R⁴O₂CC(Z)=NOH wherein R⁴ and Zare as hereinbefore defined. Preferred salts include sodium or magnesiumsalts. The reaction may be performed in an inert solvent such asdichloromethane or acetonitrile at a temperature between roomtemperature and the reflux temperature of the mixture. The salt of acompound of formula (VI) is generally prepared in situ by treating thecompound of formula (VI) with a base. Examples of suitable bases includealkaline earth metal alkoxides such as magnesium methoxide.

[0287] According to a further feature of the present invention compoundsof formula (I) in which X represents —NH— may be prepared by thedeprotection of a compound of formula (VII):

[0288] wherein R, R¹, R² and n are as hereinbefore defined and Arepresents —NX¹R³ wherein R³ is as hereinbefore defined and X¹represents a protecting group which can be removed under acidic orneutral reaction conditions. The protecting group may be for example abenzyl group (which may be removed by hydrogenolysis) or at-butyloxycarbonyl group (t-BOC). Suitable methods of protection anddeprotection are described in the literature (for example in “ProtectiveGroups in Organic Synthesis”, by T. W. Greene and P. G. M. Wuts). Theintermediates of formula (VII) are novel and as such constitute afurther feature of the present invention.

[0289] Intermediates in the preparation of compounds of formula (I) maybe prepared by the application or adaptation of known methods.

[0290] Compounds of formula (II) may be prepared by the reaction ofcompounds of formula (VI) with either a trialkyl orthoformate such astriethyl orthoformate or a dimethylformamide diallyl acetal such asdimethylformamide dimethyl acetal.

[0291] The reaction with a trialkyl orthoformate can be carried out inthe presence of acetic anhydride at the reflux temperature of themixture and the reaction with dialkylformamide dialkyl acetal is carriedout optionally in the presence of an inert solvent at a temperature fromroom temperature to the reflux temperature of the mixture.

[0292] Compounds of formula (IV) may be prepared by the reaction of acompound of formula (VIII) with a benzoyl chloride of formula (IX):

[0293] The reaction is generally carried out in the presence of anorganic base such as triethylamine in an inert solvent such as tolueneor dichloromethane at a temperature between −20° C. and roomtemperature.

[0294] Compounds of formula (V) may be prepared by the metallation ofthe appropriate acetylene of formula (X):

R¹≡CH  (X)

[0295] followed by reaction of the metal salt thus obtained with abenzoyl chloride of formula (IX). The metallation is generally performedusing n-butyl lithium in an inert solvent such as ether ortetrahydrofuran at a temperature from −78° C. to 0° C. The subsequentreaction with the benzoyl chloride is carried out in the 15 same solventat a temperature between −78° C. and room temperature.

[0296] Compounds of formula (VI) may be prepared by the reaction of anacid chloride of formula (IX) with the metal salt of a compound offormula (XI):

[0297] wherein R¹ is as hereinbefore defined, to give a compound offormula (XII):

[0298] wherein R¹, R² R³, X and n are as hereinbefore defined, which issubsequently decarboxylated to give a compound of formula (VI).Generally the reaction to produce the compound of formula (XII) isperformed in a solvent such as a lower alcohol, preferably methanol, inthe presence of a metal, preferably magnesium. The reaction may also beperformed using a pre-prepared metal salt of a compound of formula (XI).The decarboxylation is Generally performed by refluxing the compound offormula (XII) in the presence of a catalyst, such asparatoluenesulphonic acid or trifluoroacetic acid, in an inert solvente.g. toluene or 1,2-dichloroethane.

[0299] Compounds of formula (VII) may be prepared by the processeshereinbefore described for preparing compounds of formula (I) in whichR, R¹, R² and n are as hereinbefore defined and the group —XR³ isreplaced by the group A.

[0300] Acid chlorides of formula (IX) may be prepared by the reaction ofa benzoic acid of formula (XIII):

[0301] with a chlorinating agent, for example thionyl chloride at thereflux temperature of the mixture. In some cases the benzoyl chloridesmay also be prepared by reaction of the benzoic acid with oxalylchloride in a solvent such as 1,2-dichloroethane at from ambient toreflux temperature.

[0302] A number of the benzoic acids of formula (XII) are novel and assuch constitute a further feature of the present invention. Compounds offormula (XIII) in which R² represents a chlorine, bromine or iodine atomor a group selected from nitro, trifluoromethyl, methyl,trifluoromethoxy, —SMe, —SOMe, SO₂Me and —N(R⁸)SO₂R⁷; R⁷ represents astraight- or branched-chain alkyl group containing up to three carbonatoms, phenyl or benzyl; R⁸ represents a straight- or branched-chainalkyl group containing up to four carbon atoms, methoxy or phenyl; and qrepresents two, are especially preferred.

[0303] Compounds of formula (XIII) in which R³ represents —SO₂R⁷ may beprepared by the hydrolysis of the corresponding ester of formula (XIV):

[0304] wherein R^(1a) is an alkyl group and X is —NR⁸—. The reaction isgenerally carried out in the presence of a base (e.g. sodium S hydroxideor lithium hydroxide) in a solvent such as an aqueous alcohol (e.g.ethanol) at a temperature from room temperature to reflux.

[0305] Esters of formula (XIV) in which R⁸ is not hydrogen may beprepared by the reaction of the corresponding compound of formula (XIV)in which R⁸ is hydrogen with a compound of formula R⁸-L¹, wherein R⁸ isas hereinbefore defined excluding hydrogen and L¹ is a leaving group inthe presence of a base. The reaction is particularly useful forproducing esters of formula (XIV) in which R⁸ is alkyl. Generally L¹ ishalogen (preferably iodine) or —OH and the base is potassium carbonate.The reaction is performed at a temperature from room temperature toreflux in an inert solvent, preferably acetone.

[0306] Esters of formula (XIV) in which R⁸ is the same as R^(1a)may alsobe prepared from compounds of formula (XIII) in which R³ is —SO₂R⁷ andR⁸ is hydrogen by reaction with a compound of formula R^(1a)-L¹, asdescribed in the above reaction. Where L is OH optionally a mixture ofthionyl chloride with R^(1a)OH may be used.

[0307] Esters of formula (XIV) in which R⁸ is the hydrogen atom may alsobe prepared by the reaction of a compound of formula (XI) in which R⁸ ishydrogen with a compound of formula R^(1a)-OH. The reaction is performedin the presence of a strong acid (preferably concentrated sulphuricacid) optionally using the alcohol of formula R^(1a)-OH as solvent, at atemperature from ambient to reflux.

[0308] Compounds of formula (XIII) in which R³ represents —SO₂R⁷ and Xis —NH— may also be prepared by the hydrolysis of a compound of formula(XV):

[0309] wherein Z¹ is hydrogen or —SO₂R⁷, R^(1b) is alkyl or hydrogen andat least one of R^(1b) and Z¹ is not hydrogen, using a base. Preferablysodium hydroxide or lithium hydroxide is used and the reaction isconveniently performed in a solvent such as aqueous ethanol at atemperature from room temperature to reflux.

[0310] Compounds of formula (XV) in which Z¹ is hydrogen and R^(1b) isalkyl may be prepared by the hydrolysis of the corresponding compound offormula (XV) in which Z¹ is —SO₂R⁷ by the same procedure described abovefor the preparation of a compound of formula (XIII) from a compound offormula (XV) wherein the reaction is performed for a shorter period (toprevent hydrolysis of the ester group —CO₂R^(1b)).

[0311] Compounds of formula (XV) in which Z¹ is hydrogen may be preparedby the sulphonation of an aniline of formula (XVI):

[0312] using a compound of formula R⁷SO₂Cl in the presence of a base.Preferably the base used is triethylamine and the reaction is performedin an inert solvent (e.g. dichloromethane or acetonitrile) at atemperature from 0° C. to reflux. Compounds of formula (XV) in which Z¹is —SO₂R⁷ may also be prepared by this method, using an excess ofcompound of formula R⁷SO₂Cl.

[0313] Compounds of formula (XIII) in which the group —XR³ is ortho tothe acid group and R³ is —SO₂R⁷ may be prepared by the reaction of acompound of formula (XVII):

[0314] wherein X² is chlorine or preferably bromine or iodine, with acompound of formula R⁸NHSO₂R⁷ in the presence of a strong base.Generally the reaction is performed in the presence of a catalyst e.g.copper (I) chloride or preferably copper (I) bromide or iodide, in aninert solvent such as dioxan or toluene. The preferred strong base issodium hydride and the reaction is conveniently performed at atemperature from 50° C. to reflux.

[0315] Compounds of formula (XIII) in which the group XR₃ is ortho tothe acid group, R³ is —SO₂R⁷ and n is zero may be prepared by thereaction of a salt of formula (XVIII):

[0316] with a compound of formula R⁸NHSO₂R⁷ in the presence of a strongbase (e.g. sodium hydride) and a catalyst (e.g. copper acetate). Thereaction is typically performed in an inert solvent, preferablydimethoxyethane according to the methods described by R. A, Scherrer andH. R. Beatty (J. Org. Chem., Vol. 45, p2127, 1980).

[0317] Intermediates of formula (III), (V), (VIII), (X), (XI), (XIV),(XV), (XVI), (XVII) and (XVIII) are known or may be prepared by theapplication or adaptation of known methods.

[0318] Those skilled in the art will appreciate that some compounds offormula (I) may be prepared by the interconversion of other compounds offormula (I) and such interconversions constitute yet more features ofthe present invention. Examples of such interconversions are hereafterdescribed.

[0319] According to a further feature of the present invention compoundsin which p is one or two and/or q is two may be prepared by theoxidation of the sulphur atom of the corresponding compounds in which pis 0 or I and/or q is zero. The oxidation of the sulphur atom isgenerally carried out using for example 3-chloroperoxybenzoic acid in aninert solvent such as dichloromethane at a temperature from 40° C. toroom temperature.

[0320] The following examples illustrate the preparation of 10 compoundsof formula (I) and the following reference examples illustrate thepreparation of intermediates of the invention. In the presentspecification b.p. means boiling point; m.p. means melting point; cPrrepresents cyclopropyl.

EXAMPLE 1

[0321] Hydroxylamine hydrochloride (053 g) was added to a stirredsolution of1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione(2.8 g) in ethanol. Sodium acetate (0.63 g) was then added portionwiseover a period of ten minutes. The mixture was then stirred at roomtemperature for 0.5 hours. Further quantities of hydroxylaminehydrochloride (0.2 g) and sodium acetate (0.24 g) were added andstirring was continued for 0.5 hours. Water was added, the mixture wasextracted with dichloromethane and the combined organic extracts werewashed with water, dried and the solvent evaporated. The crude productwas purified by column chromatography to yield4-[2-chloro-4-(methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole(compound 1) as a white solid, 1.66 g, map. 122.8°-124.5° C.

[0322] By proceeding in a similar manner, the following compounds offormula I were prepared:— Cpd. Name m.p./NMR 24-[4-chloro-2-(N-methyl-N-methylsulphonyl)amino- 128.3-benzoyl]-5-cyclopropylisoxazole 130.8° C. 35-cyclopropyl-4-[2-(N-methyl-N-methyl- 110.8-sulphonyl)aminobenzoyl]isoxazole 113.8° C. 115-cyclopropyl-4-[2-(N-methyl-N-methyl- (a)sulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole 214-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4- (b)trifluoromethoxy]benzoyl-5-cyclopropylisoxazole 225-cyclopropyl-4-[2-(N-methyl-N-methyl- (c)sulphonyl)amino-4-trifluoromethoxy]benzoylisoxazole 234-[5-chloro-2-(N-methyl-N-methylsulphonyl)amino]- 111-benzoyl-5-cyclopropylisoxazole 113° C.

EXAMPLE 2

[0323] Hydroxylamine hydrochloride (0.76 g) was added to a mixture of1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropan-1,3-dione(3.83 g) in ethanol. The mixture was stirred for 1 hour and evaporatedto dryness. The residue was dissolved in dichloromethane and washed withwater, dried (magnesium sulphate) and filtered. The filtrate wasevaporated to dryness and the residue was purified by chromatographyeluted with a mixture of cyclohexane, dichloromethane and ethyl acetate.The product was triturated with a mixture of ether and hexane andfiltered to give4-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole(compound 4, 0.81 g) as a white solid, m.p. 114°-115.8° C.

[0324] By proceeding in a similar manner the following compounds offormula (I) were prepared from the appropriately substituted startingmaterials. m.p.(° C.) Cpd R R¹ X-R³ (R²)_(n) NMR 5 H cPr 2-N(Me)SO₂Me4-NO₂ 113-115 6 H cPr 4-N(Me)SO₂Me 2-NO₂ 116-117 7 H cPr 2-N(Me)SO₂Me4-Me 120-122 8 H cPr 2-N(nPr)SO₂Me 4-Cl 127-128 9 H cPr 2-N(Et)SO₂Me4-SO₂Me 171-172 10 H cPr 2-N(Me)SO₂Me 3,4-Cl₂ 153-154 12 H cPr2-N(Ph)SO₂Me — 114-115 13 H cPr 2-N(Me)SO₂Me 4-Br 128-130 14 H cPr2-N(Me)SO₂Me 4-SO₂Me 130-132 16 H cPr 2-N(Me)SO₂Et 4-Cl 77.5-78.5 17 HcPr 2-N(Me)SO₂Me 4-N(Me)SO₂Me 74-76 18 H cPr 2-N(Me)SO₂Me 4-F 154-155 19H cPr 4-N(Me)SO₂Me 2-Br 84-85 20 H cPr 4-N(Me)SO₂Me 2-Cl 92.4-94.2 24 HcPr 4-N(Me)SO₂Me [2-F 103-104 25 H cPr 2-N(Me)SO₂Me 3,4-diF 134-136 26 HcPr 2-N(Me)SO₂Me 4,5-diF 140-143 27 H cPr 2-N(Me)SO₂Me 41 128-129 28 HcPr 2-N(iBu)SO₂Me 4-Cl   118-118.5 29 H cPr 2-N(Me)SO₂nPr 4-Cl 112-11330 H cPr 2-N(Me)SO₂Ph 4-Cl (a) 31 H cPr 2-N—(Me)SO₂Bz 4-Cl (b) 32 H cPr2-N(Me)SO₂iPr 4-Cl 130-132 33 H cPr 2-N(OMe)SO₂Me 4-Cl 85-87

EXAMPLE 3

[0325]1-[4-Chloro-2-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione(3.8 g) and magnesium turnings (0.3 g) were stirred at room temperaturein anhydrous methanol. Reaction was initiated by adding carbontetrachloride (3 ml) and the resulting solution was stirred at roomtemperature for a further 0.5 hours and evaporated to dryness. Toluenewas added and the solution was re-evaporated to give a brown solid whichwas suspended with stirring in dry acetonitrile. The suspension washeated to 65° C. and a solution of ethyl chloroximidoacetate (2.6 g) indry acetonitrile was added dropwise over one hour. The resultingsuspension was stirred at 65° C. for a further 2 hours, then cooled toabout 40° C. Dilute hydrochloric acid (2N) was added with stirring, theresulting layers were separated and the aqueous layer was extracted withethyl acetate. The organic phases were combined, washed with brine,dried (sodium sulphate) and evaporated to give an orange oil which wascrystallised from diethyl ether to yield ethyl4-[4chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole-3-carboxylate(compound 15, 2.8 g) as a beige solid, m.p. 134°-135.6° C.

[0326] By proceeding in a similar manner ethyl5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethyl]benzoylisoxazole-3-carboxylate,compound 34 was prepared, m.p. 98°-99.5° C.

REFERENCE EXAMPLE 1

[0327] A solution of3-cyclopropyl-1-[2-(N-methyl-N-methylsulphonyl)amino4trifruoromethylphenyl]propan-1,3-dione(4.21 g) and triethylorthoformate (3.44 g) in acetic anhydride wasstirred at reflux temperature for 35 hours and then at room temperatureovernight. Excess solvents were removed by evaporation and remainingtraces of solvent were removed by azeotropic evaporation with toluene toyield3-cyclopropyl-2-ethoxymethylene-1-[2-(N-methyl-N-methylsulphonyl)aminotrifluoromethylphenyl]propan-1,3-dione as a brown oil (4.9 g).

[0328] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials.

R¹ -X-R³ (R²)_(n) cPr 4-NHSO₂Me 2-Cl cPr 4-N(Me)SO₂Me 4-Cl cPr2-N(Me)SO₂Me 3-Cl-4-OCF₃ cPr 2-N(Me)SO₂Me 4-OCF₃ cPr 2-N(Me)SO₂Me 5-ClcPr 2-N(Me)SO₂Me —

REFERENCE EXAMPLE 2

[0329] A mixture of1-[4-chloro-2-(N-ethyl-N-methyl-sulphonylamino)phenyl]-3-cyclopropylpropan-1,3-dione(3.5 g) and dimethylformamide dimethyl acetal (15ml) in dichloromethanewas stirred at room temperature overnight and heated at reflux for 3days. After cooling the mixture was evaporated to dryness to give1-[4-chloro-2-(N-ethyl-N-methylsulphonylaminophenyl]-3-cyclopropyl-2-dimethylaminomethylenepropan-1,3-dione(3.83 g) as an orange gum which was not purified further.

[0330] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials.

R¹ X-R³ (R²)_(n) cPr 2-N(Me)SO₂Me 4-NO₂ cPr 4-N(Me)SO₂Me 2-Cl cPr4-N(Me)SO₂Me 2-NO₂ cPr 2-N(Me)SO₂Me 4-Me cPr 2-N(nPr)SO₂Me 4-Cl cPr2-N(Et)SO₂Me 4-SO₂Me cPr 2-N(Me)SO₂Me 3,4-Cl₂ cPr 2-N(Ph)SO₂Me cPr2-N(Me)SO₂Me 4-SO₂Me cPr 2-N(Me)SO₂Me 4-Br cPr 2-N(Me)SO₂Et 4-Cl cPr2-N(Me)SO₂Me 4-N(Me)SO₂Me cPr 2-N(Me)SO₂Me 4-F cPr 4-N(Me)SO₂Me 2-Br cPr4-N(Me)SO₂Me 2-Cl cPr 4-N(Me)SO₂Me 2-F cPr 2-N(Me)SO₂Me 3,4-F₂ cPr2-N(Me)SO₂Me 4,5-F₂ cPr 2-N(Me)SO₂Me 4-I cPr 2-N(isobutyl)SO₂Me 4-Cl cPr2-N(Me)SO₂nPr 4-Cl cPr 2-N(Me)SO₂Ph 4-Cl cPr 2-N(Me)SO₂Bz 4-Cl cPr2-N(Me)SO₂iPr 4-Cl cPr 2-N(OMe)SO₂Me 4-Cl

REFERENCE EXAMPLE 3

[0331] A suspension of magnesium (0.47 g) in methanol was warmed gentlyto initiate reaction and then heated at reflux until all of themagnesium had dissolved. It was cooled slightly and t-butyl3-cyclopropyl-3-oxopropionate (239 g) was added. The mixture was stirredand heated at reflux for 25 minutes then evaporated to dryness. It wasdissolved in toluene and re-evaporated to dryness. The residue was againdissolved in toluene and 2-chloro-4-(methylsulphonylamino)benzoylchloride (32 g) was added. The mixture was stirred at room temperatureovernight Hydrochloric acid (2M) was added and the mixture was stirred.The layers were separated and the organic layer was dried (magnesiumsulphate) and filtered. The filtrate was evaporated to give t-butyl2-[2-chloro-4-(methylsulphonylamino)benzoyl]-3-cyclopropyl-3-oxopropionate(3.7 g) as a white solid, m.p. 137°-140° C.

[0332] t-Butyl2-[2-chloro-4-(methylsulphonylamino)benzoyl]-3-cyclopropyl-3-oxopropionate(2 g) was dissolved in toluene and p-toluenesulphonic acid (0.2 g) wasadded. The mixture was stirred and heated at reflux for 0.5 hours. Itwas cooled, washed with water, dried (magnesium sulphate) and filtered.The filtrate was evaporated to dryness to give1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropylpropan-1,3-dione(1.48 g) as a white solid, m.p. 119.9°-121.6° C.

[0333] By proceeding in a similar manner the following compounds offormula (VI) above were prepared from the appropriately substitutedstarting materials without isolation of the intermediate ester. m.p. (°C.) or R X-R³ (R²)_(n) NMR cPr 2-N(Me)SO₂Me 4-Cl 93.3-96.5 cPr2-N(Me)SO₂Me 4-NO₂ — cPr 2-N(Et)SO₂Me 4-Cl a cPr 4-N(Me)SO₂Me 2-Cl — cPr4-N(Me)SO₂Me 2-NO₂ — cPr 2-N(Me)SO₂Me 4-Me b cPr 2-N(nPr)SO₂Me 4-Cl ccPr 2-N(Et)SO₂Me 4-SO₂Me d cPr 2-N(Me)SO₂Me 3,4-Cl₂ — cPr 2-N(Ph)SO₂Me ecPr 2-N(Me)SO₂Me 4-CF₃ — cPr 2-N(Me)SO₂Me 4-N(Me)SO₂Me f cPr2-N(Me)SO₂Et 4-F g cPr 4-N(Me)SO₂Me 2-Cl — cPr 2-N(Me)SO₂Me 4-SO₂Me hcPr 2-N(Me)SO₂Me 3-Cl-4-OCF₃ i cPr 2-N(Me)SO₂Me 4-OCF₃ j cPr2-N(Me)SO₂Me 5-Cl k cPr 2-N(Me)SO₂Me 4,5-F₂ 104-105 cPr 2-N(Me)SO₂Me 4-I131.5-134   cPr 2-N(Me)SO₂Me — 110-113

REFERENCE EXAMPLE 4

[0334] For the following diketones of formula (VI) an alternativedecarboxylation method was used, the corresponding t-butyl2-aroyl-3-cyclopropyl-3-oxopropionate being prepared as described above.t-Butyl2-[4chloro-2-(N-ethylsulphonyl-N-methyl)aminobenzoyl]-3-cyclopropyl-3-oxopropionatewas dissolved in 1,2-dichloroethane. The solution was stirred andtrifluoroacetic acid (1.5 equivalent) was added. The mixture was stirredat room temperature for 3 hours then evaporated to dryness. The residuewas purified by column chromatography (ethyl acetate/cyclohexane/dichloromethane) to yield1-[4-chloro-2-(N-ethylsulphonyl-N-methyl)aminophenyl]-3-cyclopropylpropan-1,3-dione(6.79 g) as a red oil, NMR (CDCl3) 1.05 (m,2H), 1.2(m,2H), 1.41(t,3H),1.77(m,1H), 3.16(q,2H), 328(s,3H), 6.1(s,1H), 7.4(dd,1H), 7.47(d,1H),7.65(d,1H), 16.05(bs,0.5H).

[0335] By proceeding in a similar manner the following compounds offormula (VI) above were prepared from the appropriately substitutedstarting materials:

[0336]1-[4-bromo-2-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione,m.p. 120°-122° C.;

[0337]1-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione,NMR (CDCl3) 1.03(m,2H), 1.23(m,2H), 1.77(m,1H), 2.9(s,3H), 3.37(s,3H),6.08(s,1H) 7.45(dd,1H), 7.58(d,₁H), 7.67(d,1H), 15.87(bs,0.5H);

[0338]1-cyclopropyl-3-([2-fluoro4-(N-methyl-N-methylsulphonyl)-aminophenyl]-propan-1,3-dioneas a yellow solid (using toluene as the solvent in place of1,2-dichloroethane);

[0339]1-cyclopropyl-3-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethylphenyl]propan-1,3-dioneas a brown gum (using dichloromethane as the solvent in place of1,2-dichloroethane);1-[4-chloro-2-(N-methyl-N-propylsulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione.

[0340] Benzoyl chlorides were prepared by heating the appropriatelysubstituted benzoic acids with thionyl chloride. The excess thionylchloride was removed by evaporation the benzoyl chlorides thus obtainedwere used without further purification. In some cases the benzoylchlorides were prepared by reaction of the benzoic acid with oxalylchloride in 1,2-dichloroethane at ambient temperature. Evaporation ofthe solvents in vacuo gave the corresponding benzoyl chlorides.

REFERENCE EXAMPLE 5

[0341] 2N Sodium hydroxide solution (20 ml) was added to a stirredsolution of methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)-benzoate(2.75 g) in methanol. The mixture was stirred at reflux for 05 hours.After cooling, the mixture was acidified with 2N hydrochloric acid andextracted with ethyl acetate. The organic extracts were combined, driedand evaporated to yield4chloro-2-(N-methyl-N-methylsulphonylamino)benzoic acid as a white solid(2.45 g), m.p. 161°-164° C.

[0342] By proceeding in a similar manner, the following compounds wereprepared:—

[0343] 2-(N-methyl-N-methylsulphonylamino) 4nitrobenzoic acid NMR(DMSO-d₆) 3.1(s,3H) 3.3(s,3H) 7.95(d,1H) 8.3(d,1H) 8.4(s,1H)13.3-13.8(bs,1H);

[0344] 4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoic acid m.p.148°-151° C.;

[0345] 2-chloro4-(N-methyl-N-methylsulphonylamino)benzoic acid m.p.152°-153° C.;

[0346] 4-(N-methyl-N-methylsulphonylamino)-2-nitrobenzoic acid m.p.177°-178.6° C.;

[0347] 4-methyl-2-(N-methyl-N-methylsulphonylamiino)benzoic acid m.p.185°-187° C.;

[0348] 4-chloro-2-(N-methylsulphonyl-N-propyl)aminobenzoic acid, m.p.133°-135° C.;

[0349] 3,4-dichloro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid,m.p. 118°-119.4° C.;

[0350] 2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethyl-benzoicacid, m.p. 157°-160° C.;

[0351] 4-bromo-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.181°-182° C.;

[0352] 4-chloro-2-(N-ethylsulphonyl-N-methyl)aminobenzoic acid, m.p.132°-134° C.;

[0353] 2-bromo4(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.153.5°-155.5° C.;

[0354] 2,4-bis(N-methyl-N-methylsulphonyl)aminobenzoic acid, NMR(CDCl₃); 2.8 (s,3H), 2.9(s,3H), 3.23(s,3H), 3.3(s,3H), 7.4(dd,1H),7.48(d,1H), 8.03(d,1H);

[0355] 4fluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, NMR(CDCl₃); 3.06(s,3H), 3.28(s,3H), 7.1-73(m,2H), 8.1(m1H);

[0356] 2-fluoro4-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.189°-191° C.;

[0357] 3,4-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid,m.p. 159.5°-161° C.;

[0358]3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenzoicacid, NMR(CDCl₃) 3.0(s,3H), 33(s,3H), 6.7 (brs,1H), 7.4(m,1H),8.0(d,1H);

[0359] 2-(N-methyl-N-methylsulphonyl)amino4-trifluoromethoxybenzoicacid, m.p. 138.5°-141° C.;

[0360] 5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid.NMR(DMSOd₆) 3.0(s,3H), 3.2(s,3H), 7.6(d,1H), 7.65(m,1H), 7.75(m,1H);

[0361] 4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminobenzoic acid, m.p.158°-159° C.,

[0362] 4-chloro-2-(N-methyl-N-propylsulphonyl)aminobenzoic acid, m.p.143.5°-144.5° C.;

[0363]4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoic acid, m.p.180°-181° C.;

[0364] 4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoic acid, m.p.180°-185° C.

[0365] 2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p. 146°-149°C.

REFERENCE EXAMPLE 6

[0366] Potassium carbonate (125 g) was added to a stirred solution ofmethyl 4chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in acetone.The mixture was stirred for 15 minutes and methyl iodide (8.0 g) wasadded. The resultant mixture was stirred at room temperature for 1 hourand left to stand overnight. The mixture was evaporated to dryness andthe residue was dissolved in ethyl acetate and washed with sodiumhydroxide solution (2M) and water, dried (anhydrous magnesium sulphate)and filtered. The filtrate was evaporated to dryness to give methyl4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (4.9 g) as a whitesolid, m-p. 73°-75° C.

[0367] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0368] methyl 2-chloro4(N-methyl-N-methylsulphonylamino)-benzoate, NMR(DMSO-d₆) 3.05(s,3H) 3.35(s,3H) 3.85(s,3H) 7.5(d,1H) 7.6(s,1H)7.85(d,1H);

[0369] methyl 2-(N-methyl-N-methylsulphonylamino)-4 nitrobenzoate, NMR(DMSO-d₆) 3.05(s,3H) 3.25(s,3H) 3.8(s,3H) 8.0(d,1H) 83(d,1H) 8.4(s,1H);

[0370] ethyl 4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoate, NMR(CDCl₃) 1.1(t,3H) 1.35(t,3H) 2.9(s,3H) 3.65(q,2H) 4.3(q,2H) 7.3(d,1H)7.35(s,1H) 7.8(d,1H);

[0371] methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate,NMR (CDCl₃); 2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H), 7.71(d,1H);

[0372] methyl2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenzoate, NMR(CDCl₃) 2.95(s,3 H), 3.3(s,3H), 3.95(s,3H), 7.25(m,2H), 8.0(d,1H);

[0373] methyl 5-chloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate,m.p. 91°-93° C.;

[0374] methyl 4-chloro-2-(N-isobutyl-N-methylsulphonyl)-aminobenzoate,m.p. 89°-90° C., employing isobutyl iodide instead of methyl iodide;

[0375] methyl 4-chloro-2-(N-methyl-N-propylsulphonyl)-aminobenzoate asan orange oil;

[0376] methyl 2-(N-methyl-N-methylsulphonyl)-aminobenzoate, m.p. 60°-62°C.

REFERENCE EXAMPLE 7

[0377] Methyl iodide (22.0 ml) was added to a stirred suspension of4-methyl-2-(N-methylsulphonylamino)benzoic acid (8.0 g) and anhydrouspotassium carbonate (24.2 g) in acetone and the mixture was stirred andheated at reflux overnight. The mixture was cooled and filtered and thefiltrate was evaporated to dryness. The residue was dissolved indichloromethane and washed with aqueous sodium bicarbonate solution,water, dried (magnesium sulphate) and filtered. The filtrate wasevaporated to dryness to give methyl4-methyl-2-(N-methyl-N-methylsulphouylamino)benzoate (8.36 g) as a creamsolid, m.p. 100°-103° C.

[0378] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0379] methyl 4-(N-methyl-N-methylsulphonylamino)-2-nitrobenzoate, NMR(CDCl₃) 2.95(s,3H) 3.4(s,3H) 3.9(s,3H) 7.7(d,1H) 7.75(d,1H) 7.85(s,1H);propyl 4-chloro-2-(N-methylsulphonyl-N-propylamino)-benzoate m.p.81°-83° C.;

[0380] ethyl2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonyl-benzoate m.p.108.6°-109.4° C.;

[0381] methyl2-(N-methyl-N-methylsulphonyl)amino4-trifluoromethylbenzoate, NMR(CDCl₃) 2.93(s,3H). 3.3(s,3H), 3.9(s,3H), 7.65(m,2H), 8.0(dd, 1H);

[0382] methyl 4-bromo-2-(N-methyl-N-methylsulphonnyl)-aminobenzoate NMR(CDCl₃) 2.95(s,3H), 3.23(s,1H), 3.83(s,3H), 7.5(dd,1H), 7.58(d,1H),7.75(d,1H);

[0383] methyl 4-chloro-2-(N-ethylsulphonyl-N-methyl)amino-benzoate;

[0384] methyl 2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoate, NMR(CDCl₃); 2.9(s,3H), 3.38(s,3H), 3.93(s.3H), 7.46(dd, 1H), 7.68(d, 1H),7.87(d, 1H);

[0385] methyl 2,4-bis(N-methyl-N-methylsulphonyl)aminobenzoate NMR(CDCl₃); 2.9(s,3H), 2.96(s,3H), 3.23(s,3H), 3.79(s,3H), 3.87(s,3H),7.42(dd,1H), 7.48(d,1H), 7.95(d,1H);

[0386] methyl 4-fluoro-2-(N-methyl-N-methylsulphonyl)amino-benzoate NMR(CDCl₃); 2.97(s,3H), 3.23(s,3H), 3.87(s,3H), 7.06-7.24(m,2H),7.96(m,1H);

[0387] methyl 2-(N-methyl[-N-methylsulphonyl)amino4-methylsulphonylbenzoate NMR (acetone-d₆); 3.02 (s,3H), 3.22(s,3H),3.35(s,3H), 3.9(s,3 H), 8.06(m,2H), 8.17(m,1H);

[0388] methyl 2-fluoro-4( N-methyl-N-methylsulphonyl)-aminobenzoate asan orange oil, NMR (CDCl₃) 2.89(s,3H), 3.34(s,3H), 3.91(s,3H),7.1(m,2H), 7.93(t,1H);

[0389] methyl 3,4-difluoro-2-(N-methyl-N-methylsulphonyl)-aminobenzoateas an orange solid, NMR (CDCl₃) 3.01(s,3H), 3.3(s,3H), 3.91(s,3H),7.24(q,1H), 7.73(m,1H);

[0390] methyl 4-chloro-2-( N-methyl-N-phenylsulphonyl)-aminobenzoate asa white solid, m.p. 100°-107° C.;

[0391] methyl4-chloro-2-(.i-methyl-N-benzylsulphonyl-N-methyl)aminobenzoate as acream solid, m.p. 89°-91° C.

REFERENCE EXAMPLE 8

[0392] A solution of methanesulphonyl chloride (6.3 g) indichloromethane was added to a stirred, cooled (0°-5° C.) solution ofmethyl 2-amino-4-chlorobenzoate (9.5 g) in dichloromethane.Triethylamine (7.1 g) was then added and the mixture was stirred at0°-5° C. for 10 minutes and then at room temperature for 0.5 hours.

[0393] The mixture was diluted with 2N hydrochloric acid. The organicphase was separated, washed with water, dried and evaporated. The crudeproduct was purified by column chromatography to yield methyl4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid. (3.6 g)m.p. 125.5°-128.1° C.

[0394] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0395] methyl2-(N-methyl-N-methylsulphonyl)amino-4-(N,N-bis-methylsulphonylamino)benzoateas an orange gum, NMR (CDCl₃) 2.57(s,3 H), 3.)(s,3 H), 3.4(s,6H),3.94(s,3H), 7.4(m,1H), 7.5(m,1H), 7.97(d, 1H):

[0396] methyl 2-(N-methylsulphonylamino)benzoate, m.p. 88°-90° C.

REFERENCE EXAMPLE 9

[0397] Concentrated sulphuric acid (20 ml) was added to a suspension of2-chloro4-(N-methylsulphonylamino)benzoic acid (10.3 g) in methanol andthe mixture was stirred and heated at reflux for 22 hours. It wascooled, evaporated to dryness and diluted with water, extracted withethyl acetate, washed with aqueous sodium bicarbonate solution, water,dried (magnesium sulphate) and filtered. The filtrate was evaporated todryness to give methyl 2-chloro4-(N-methylsulphonylamino)benzoate(10.0g) as an off-white solid, NMR (DMSO-d₆) 3.15(s,3H) 3.85(s,3H) 7.2(d.1H)7.3(s,1H) 7.85(d, 1H) 10.5(s, 1H),

[0398] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0399] methyl 2-(N-methylsulphonylamino)4-nitrobenzoate, NMR (CDCl₃):3.15 (s,3H) 4.0(s,3H) 7.9(d,1H) 8.25(d,1H) 8.5(s,1H) 10.65(s,1H);

[0400] methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate,NMR (CDCl₃); 2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H), 7.71(d,1H);

[0401] methyl 2-chloro-4-(N-methyl-N-methylsulphonyl)amino-benzoate, NMR(DMSO d₆) 3.0(s,3H), 3.35(s,3H), 3.82(s,3H), 7.5(dd, 1H), 7.63(d,1H),7.87(d,1H),

[0402] methyl 2-amino-4-trifluoromethylbenzoate m.p. 60°-62° C.;

[0403] methyl 2-amino4-methylbenzoate m.p. 41°-43° C.;

[0404] methyl 4-bromo-2-nitrobenzoate m.p. 41°-43° C.;

[0405] methyl 2-bromo-4-nitrobenzoate m.p. 83°-85° C.;

[0406] methyl 2-amino-3,4-dichlorobenzoate, NMR (CDCl₃): 3.9(s,3H),6.4(bs,2H), 6.7-7.7(m,2H);

[0407] methyl 2-amino-3,4-difluorobenzoate.

REFERENCE EXAMPLE 10

[0408] A mixture of ²-chloro-4-(N-methylsulphonylamino)benzoic acid and2-chloro-4-[N,N-bis(methylsulphonyl)amino]benzoic acid (3.6 g) inaqueous sodium hydroxide (2M) and methanol was stirred and heated atreflux for 0.5 hours. It was cooled and the methanol - was removed byevaporation. The aqueous residue was acidified and the product wasfiltered off to give 2-chloro-4-(N-methylsulphonylamino)benzoic acid(3.4 g) as a white solid, m.p. 256°-258° C.

[0409] By proceeding in a similar manner the following compounds 10 wereprepared from the appropriately substituted starting materials:2-(N-methylsulphonylamino)4-nitrobenzoic acid, NMR (DMSO-d₆) 3.3(s,3H)7.9(d,1H) 8.2(d,1H) 8.35(s,1H) 10.5-11.1(bs,1H);

[0410] N-(methylsulphonyl)aniline, starting from[N,N-(bis)methylsulphonyl]aniline.

REFERENCE EXAMPLE 11

[0411] An aqueous solution of sodium hydroxide (11.0 g) was added to asolution of a mixture of methyl4-methyl-2-(N,N-bis(methylsulphonyl)amino]benzoate and methyl4-methyl-2-(N-methylsulphonylamino)benzoate (23.26 g) in methanol andthe resulting suspension was heated at reflux for 1 hour. It was cooledand the methanol was removed by evaporation. The aqueous solution wasacidified and the resultant solid was filtered off to give4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a creamsolid, m.p. 202°-205° C.

[0412] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0413] 4-(N-methylsulphonylamino)-2-nitrobenzoic acid, NMR (DMSO-d₆)3.2(s,3H) 7.5(d,1H) 7.6(s,1H) 7.9(d,1H) 10.8(s,1H) 13.3-14.1(bs,1H);

[0414] 4-bromo-2-(N-methylsulphonyl)aminobenzoic acid m.p. 178°-186° C.;

[0415] 4-chloro-2-(N-ethylsulphonyl)aminobenzoic acid m.p. 177°-179° C.;

[0416] 2-bromo-4-(N-methylsulphonyl)aminobenzoic acid m.p.-244°-245° C.;

[0417]4-fluoro-2-( N-methylsulphonyl)aminobenzoic acid NMR (DMSO-d₆)3.33(s,3H), 7.0(m,1H), 7.36(dd, H), 8.08(m.1H), 10.92(brs,0.5H);

[0418] 2-chloro-4-( N-methylsulphonyl)aminobenzoic acid NMR (DMSO-d₆)3.1(s,.3H), 7.24(dd,1H), 7.29(d,1H), 7.85(d.1H), 10.38(brs,1H),13.08(bs,1H),

REFERENCE EXAMPLE 12

[0419] Methanesulphonyl chloride (5.72 g) was added to a stirred, cooled(0° C.) mixture of 4-amino-2-chlorobenzoic acid (6.9 g) andtriethylamine (13.1 g) in acetonitrile. The mixture was then stirred atroom temperature for 3.5 hours. Triethylamine (4 g) was added and themixture was cooled to 0° C. and further methanesulphonyl chloride (3.8g) was added. The mixture was then stirred at room temperature for onehour. The mnixture was filtered and the filtrate evaporated. The residuewas dissolved in 2N sodium hydroxide solution and washed with diethylether. The aqueous solution was acidified to pH 2-3 with 2N hydrochloricacid and then extracted with ethyl acetate. The organic extracts wereevaporated. The residue was triturated with diethyl ether to yield amixture of 2-chloro4-(N-methylsulphonylamino)benzoic acid and2-chloro-4-[N,N-bis(methylsulphonyl)amino]benzoic acid.

REFERENCE EXAMPLE 13

[0420] Methanesulphonyl chloride (12.2 ml) was added to a stirred,cooled solution of methyl 2-amino-4-methylbenzoate (10.3 g) andtriethylamine (19.5 ml) in dichloromethane while maintaining thetemperature below 0° C. The mixture was stirred at room temperature for4 hours. Hydrochloric acid (2M) was added and the layers were separated.The organic layer was washed with water, dried (magnesium sulphate) andfiltered. The filtrate was evaporated to dryness to give a mixture ofmethyl 4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl4-methyl-2-(N-methylsulphonylamino)benzoate (18.26 g) as a yellow solidwhich was not further purified.

[0421] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0422] 4-[N,N-bis-(methylsulphonyl)amino]-2-nitrobenzoic acid;

[0423] methyl2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonyl-benzoate;

[0424] N,N-bis(methylsulphonyl)aniline, m.p. 172°-177.6° C.,

[0425] methyl2-[N,N-bis(methylsulphonyl)]amino-4-trifluoromethyl-benzoate m.p.159°-163° C.;

[0426] methyl 4-bromo-2-[N,N-bis( methylsulphonyl)]aminobenzoate, m.p.221°-225° C.;

[0427] methyl 4-chloro-2-( N-ethylsulphonyl)amino]benzoate and

[0428] methyl 4-chloro-2-]N,N-bis(ethylsulphonyl)amino]benzoate:

[0429] methyl 2-bromo4-[N,N-bis(methylsulphonyl)amino]benzoate and

[0430] methyl 2-bromo4-(N-methylsulphonyl)aminobenzoate;

[0431] methyl 2-(methyl-N-methylsulphonyl)amino-4-N,N-bis(methylsulphonyl)aminobenzoate, NMR(CDCl₃), 2.97(s,3H), 3.32(s,3H),3.38(s,6H), 3.92(s,3H), 7.43(dd,1H), 7.52(d,1H), 7.98(d,1H);

[0432] methyl 4-fluoro-2-[N,N-bis(methylsulphonyl)amino]benzoate NMR(CDCl₃); 3.5(s,6H), 3.95(s,3H), 7.16(dd.1H) 7.27(m,1H), 8.06(m, 1H);

[0433] methyl 2-chloro4-[N,N-bis(methylsulphonyl)amino]benzoate NMR(CDCl₃): 3.43(s,6H), 3.92(s,3H), 7.3;(dd,1H), 7.47(d,1H), 7.9(d,1H);

[0434] methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate m.p. 207.4°-211.2° C.;

[0435] methyl-2-(N,N-bis(methylsulphonyl)amino]-4-nitrobenzoate as ayellow solid. NMR (CDCl₃) 3.5(s,6H), 4.0(s,3H), 8.18(d.1H), 8.26(m,1H),8.39(m,1H);

[0436] methyl 2-fluoro-4-[N,N-bis(methylsulphonyl)amino]benzoate as awhite solid. NMR (CDCl₃) 3.42(s,6H), 3.95(s,3H), 7,21(m.2H), 8.04(t,1H);

[0437] methyl 3.4-difluoro-2-[N,N-bis( methylsulphonyl)amino]-benzoateas a solid, NMR (CDCl₃) 3.42(s,6H), 3.S7(s,3H), 7.3(q.1H), 7.79(m,1H):

[0438] methyl2-[N,N-bis(methylsulphonyl)amino]-4-trifluoromethylbenzoate as an orangeoil;

[0439] methyl 2-(N-methylsulphonyl)amino-4-trifluoromethoxybenzoate andmethyl 2-[N,N-bis(methylsulphonyl)-amino]-4-trifluoromethoxybenzoate;

[0440] methyl 5-chloro-2-(N-methylsulphonyl)aminobenzoate and methyl5-chloro-2-[N,N-bis(methylsulphonyl)amino]benzoate, m.p. 136°-138° C.;

[0441] methyl 4-chloro-2-[N,N-bis(propylsulphonyl)amino]benzoate as abrown oil;

[0442] methyl 4-chloro-2-[N,N-bis-(phenylsulphonyl)amino]benzoate as acream solid, m.p. 156.5°-158° C.;

[0443] methyl 2-[N,N-bis-(benzylsulphonyl)amino]-4-chlorobenzoate as abrown solid.

REFERENCE EXAMPLE 14

[0444] A mixture of ethyl2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate (11.4 g)and lithium hydroxide monohydrate (1.37 g) in aqueous ethanol (50%) wasstirred at room temperature for 19 hours. The mixture was then acidifiedwith conc. hydrochloric acid and extracted with ethyl acetate. Thecombined organic extracts were dried (magnesium sulphate), filtered andevaporated to yield2-(N-ethyl-N-methylsulphonyl-amino)-4-methylsulphonylbenzoic acid as abrown solid (9.48 g), NMR (acetone-d₆); 1.15(t,3H), 2.98(s,3H),3.22(s,3H), 3.85(q,2H), 8.0-8.25(m.3H),

[0445] By proceeding in a similar manner2-(N-methyl-N-methylsulphonyl)amino4-methylsulphonylbenzoic acid wasprepared, m.p. 199°-200° C.

REFERENCE EXAMPLE 15

[0446] A suspension of methyl2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) andlithium hydroxide monohydrate (7.5 g) in aqueous methanol (50) wasstirred at room temperature for 18 hours. The resulting solution wasacidified with concentrated hydrochloric acid and extracted with ethylacetate. The combined organic extracts were dried (magnesium sulphate),filtered and evaporated to yield2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid.NMR (acetone d₆): 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H),

[0447] By proceeding in a similar manner the following compounds wereprepared from the appropriately substituted starting materials:

[0448] 2-(N-methylsulphonyl)amino-4-trifluoromethylbenzoic acid as anorange oil;

[0449]2-(N-methyl-N-methylsulphonyl)amino4-(N-methylsulphonylamino)benzoicacid as an orange solid;

[0450] 2-(N-methylsulphonyl)amino4-methylsulphonylbenzoic acid.

[0451] The following compounds were prepared using sodium hydroxide inplace of lithium hydroxide:

[0452] 2-(N-methylsulphonyl)amino-4-nitrobenzoic acid as an orangesolid;

[0453] 2-fluoro4-(N-methylsulphonyl)aminobenzoic acid as a brown solid,NMR (DMSO) 3.26(s,3H), 7.04(m,2H), 7.85(t,1H), 10.5(s,1H), 13.0(s,1H);

[0454] 3,4-difluoro-2-(N-methylsulphonyl)aminobenzoic acid as a brownsolid;

[0455] 4-chloro-2-(N-propylsulphonyl)aminobenzoic acid, m.p. 159°-160°C.;

[0456] 4-chloro-2-(N-phenylsulphonyl)aminobenzoic acid, m.p. 186.5°-189°C.;

[0457] 4-chloro-2-(N-benzylsulphonyl)aminobenzoic acid, m.p. 181°-185°C.

REFERENCE EXAMPLE 16

[0458] Concentrated hydrochloric acid (90 ml) was added to a stirredsuspension of methyl 2-nitro 4methylsulphonyl benzoate (25. g) inmethanol at −50° C. (ice/salt bath). The cooling bath was then removedand iron dust (17.5 g) was added portionwise over a period of 20minutes. The resulting exotherm was controlled using a cooling bath sothat the temperature did not exceed 50° C. After 15 minutes of cooling,the bath was removed and the reaction mixture was allowed to reach roomtemperature. Stirring was continued for a further 3 hours. The mixturewas poured onto ice and then neutralised with sodium carbonate.Dichloromethane was added and the suspension was filtered. The filtratewas extracted with further dichloromethane and the combined organicextracts were dried (magnesium sulphate), filtered and evaporated toyield a crude product which was purified by recrystallisation from ethylacetate/hexane to give methyl 2-amino-4-methylsulphonyl benzoate (4.5 g)as yellow needles, m.p. 98.3°-98.5° C.

[0459] By proceeding in a similar manner, the following compounds wereprepared from the appropriately substituted starting material:

[0460] methyl 2-amino-4-bromobenzoate NMR (CDCl₃) 3.8(s,3H),5.72(bs,2H), 6.7(dd,1H), 6.79(d,1H), 7.65(d,1H);

[0461] methyl 4-amino-2-bromobenzoate m.p. 93°-95° C.

REFERENCE EXAMPLE 17

[0462] A mixture of methyl 2-amino-3,4-dichlorobenzoate (2.2 g) andmethanesulphonyl chloride (2.86 g) was stirred at 100° C. for 4 hours. Afurther quantity of methanesulphonyl chloride (2.86 g) was added and themixture was stirred at 100° C. overnight. The mixture was poured intowater then extracted with ethyl acetate. The combined organic extractswere washed with water, dried (magnesium sulphate) and evaporated toyield a brown oil which was crystallised from cyclohexane/ethyl acetateto yield methyl 3,4-dichloro-2-(methylsulphonylamino)benzoate as lightbrown crystals (1.4 g), m-p. 100°-102° C.

REFERENCE EXAMPLE 18

[0463] A solution of N-(methylsulphonyl)aniline (455 g) indimethoxyethane was added under an inert atmosphere to a stirredsuspension of sodium hydride (80% oil dispersion, 0.8 g) indimethoxyethane at room temperature. The resulting white emulsion wasstirred at 37° C. for 30 minutes. Diphenyliodonium-2-carboxylatemonohydrate (10 g) and cupric acetate (0.3 g) were then added and thesuspension was stirred at reflux for 24 hours. The mixture was cooled toroom temperature and water was added. The mixture was made alkaline byaddition of 2M NaOH solution then filtered through ‘HYFLO’ silica. Thefiltrate was acidified with concentrated hydrochloric acid and thenextracted with ethyl acetate. The combined organic extracts were dried(magnesium sulphate) and evaporated to yield2-(N-methylsulphonyl-N-phenyl)aminobenzoic acid.

REFERENCE EXAMPLE 19

[0464] A suspension of 4-bromo-2-nitrotoluene (50 g) in water was heatedto 97° C. Potassium permanganate (240 g) was then added over a period of4.5 hours. The resulting suspension was heated at reflux overnight. Themixture was filtered whilst hot (through ‘HYFLO’ silica). The filtercake was washed through with boiling water. The cooled filtrates werewashed with diethyl ether then acidified to pH 1 with concentratedhydrochloric acid. The resulting-suspension was cooled in ice water andthen filtered. The solid was dried to yield 4-bromo-2-nitrobenzoic acid(10.83 g) as a cream solid, m.p. 164°-167° C.

REFERENCE EXAMPLE 20

[0465] A suspension of methyl2-(N-methyl-N-methylsulphonyl-amino)4-nitrobenzoate (2.88 g), ironpowder (5 g) and calcium chloride (0.5 g) in ethanol was stirred atreflux for 2 hours. The suspension was filtered whilst hot. The filtercake was thoroughly washed with boiling ethanol. The combined filtrateswere cooled to room temperature then evaporated to dryness to yieldmethyl,4-amino-2-(N-methyl-N-methylsulphonyl)-aminobenzoate (3 g) as alight brown solid, NMR (CDCl₃); 3.0 (s,3H), 3.21(s,3H), 3.8(s,3H),3.6-4.15(bs,2H), 6.6(dd,1H), 6.7(d,1H), 7.83(d,1H),

REFERENCE EXAMPLE 21

[0466] Sodium hydride (60% oil dispersion, 1.0 g) was stirred in drytoluene under an inert atmosphere and methanesulphonamide (0.8 g) wasadded. After heating at reflux for 1 hour and cooling,2-bromo-3-chloro-4-trifluoromethoxybenzoic acid (2.69 g) was added.After the effervescence had subsided, copper (I) bromide (0.72 g) wasadded and the mixture heated at reflux for 8 hours. Two furtheradditions of copper (I) bromide (total 1.42 g) were made, with refluxmaintained for a further 12 hours. After cooling, a solution ofpotassium bisulphate was added and the mixture-extracted (ethylacetate), dried (magnesium sulphate) and evaporated to dryness to give3-chloro-2-(N-methylsulphonyl)-amino-trifluoromethoxybenzoic acid as awhite solid (4.14 g). This was used without further purification in thenext stage according the following procedure.

[0467] This product (1.7 g) was heated at reflux for 10 hours withstirring with methyl iodide (3.68 ml) and anhydrous potassium carbonate(4.14 g) in acetone. Additional methyl iodide (26 ml) was added withheating at reflux for 12 hours. The solvent was evaporated in vacuo andthe residue partitioned between water and dichloromethane. The organiclayer was dried (magnesium sulphate) and evaporated to give methyl3-chloro-2-(N-methyl-N-methylsulphonyl)4-trifluoromethoxybenzoate (1.73g) as an oil, NMR (CDCl₃) 2.95(s,3H), 3.25(s,3H), 3.90(s,3H),7.35(m,1H), 7.80(d, 1H),

REFERENCE EXAMPLE 22

[0468] A solution of 3-chloro1trifluoromethoxybenzoic acid (4.15 g) indry tetrahydrofuran was treated with n-butyl lithium (15.1 ml of 2.5Msolution in hexanes) at 78° C. under an inert atmosphere. After stirringovernight at this temperature, a solution of1,2-dibromotetrachloroethane (8.39 g) in tetrahydrofuran was added.After 30 minutes, the solution was allowed to slowly warm to is .15ambient temperature, then treated with 2M hydrochloric acid. Themixture was extracted with ether, the ethereal solution itself extractedwith sodium bicarbonate solution and the latter acidified with dilutehydrochloric acid. This solution was extracted with ether and evaporatedin vacuo to give 2-bromo-3-chloro4-trifluoromethoxybenzoic acid (55 g)as a brown solid, NMR (CDCl₃) 73(m,1H), 7.8(d,1H).

REFERENCE EXAMPLE 23

[0469] A solution of n-butyl lithium (4.4 ml of 25M solution in hexanes)in dry diisopropyl ether was treated at −78° C. under an inertatmosphere with 3-chloro4-trifluoromethoxy-bromobenzene (2.96 g) indiisopropyl ether. After 10 minutes, excess carbon dioxide (in the formof pellets) was added and the mixture left to slowly warm to ambienttemperature. Ice-water was added and the organic layer run off. Theaqueous layer was acidified with dilute hydrochloric acid, extracted(ether), dried (magnesium sulphate) and evaporated to dryness to give3-chloro-4-trifluoromethoxybenzoic acid (1.51 g) as a white solid, m.p.110.5°-111.5° C.

REFERENCE EXAMPLE 24

[0470] A solution of 3-chloro4-trifluoromethoxyaniline (5.1 g) in aceticacid (31 ml) was stirred and treated with sodium nitrite (2.16 g) inconcentrated sulphuric acid (14 ml) at below 18° C. After an additional1 hour at 10° C., the solution was added to a mixture of copper (I)bromide (7.7 g) and hydrobromic acid (24.5 ml) in water at 40°-50° C.The reaction was completed by heating at 50° C. for 2 hours, water wasadded and the mixture filtered. The filtrate was extracted with ether,washed with sodium bicarbonate, dried (magnesium sulphate) andevaporated to give 3-chloro4-trifluoromethoxy-bromobenzene (6.05 g) as abrown oil, NMR (CDCl₃) 7.10(m,1H), 7.35(m,1H), 7.35(d,1H),

[0471] By proceeding in a similar manner2-nitro4-trifluoromethoxy-bromobenzene was prepared, NMR (CDCl₃)7.35(m,1H), 7.75(m,1H), 7.8(d,1H),

REFERENCE EXAMPLE 25

[0472] A solution of anhydrous tin (II) chloride (17.14 g) inconcentrated hydrochloric acid was added to a solution of3-chloro-4-trifluoromethoxy-nitrobenzene (5.2 g) in ethanol with coolingto maintain a temperature below 30° C. After an additional 2 hours atambient temperature and 05 hour at 50° C., the mixture was poured ontowater, basified with sodium hydroxide solution and extracted with ether.The extracts were washed with water, dried (magnesium sulphate) andevaporated in vacuo to give an oil (6.2 g), which was purified bychromatography eluting with dichloromethane to give3-chloro-4-trifluoromethoxyaniline (4.1 g), m.p. 32°-33° C. as a yellowsolid.

REFERENCE EXAMPLE 26

[0473] A stirred mixture of 2-trifluoromethoxy-5-nitroaniline (8.61 g)and concentrated hydrochloric acid in water was stirred at 0° C. andtreated with sodium nitrite (2.93 g) in water (7ml). After 1 hour at 0°C. the solution was added to a stirred solution of copper (I) chloride(4.4 g) in water and concentrated hydrochloric acid keeping below 20° C.After stirring overnight the mixture was diluted with water, extractedwith ether and the extracts dried (magnesium sulphate) and evaporated togive an oil (8.7 g). This was purified by chromatography eluting withhexane/ethyl acetate (98:2) to give3-chloro4-trifluoromethoxy-nitrobenzene (5.2 g) as a yellow liquid, NMR(CDCl₃) 7.50(m,1H), 8.20(m,1H), 8.4(d,1H),

REFERENCE EXAMPLE 27

[0474] A mixture of potassium hydroxide (4.71 g) and5-nitro-2-trifluoromethoxyacetanilide (20 g) in ethanol and water washeated at reflux for 3.5 hours, poured onto ice and the resulting solidfiltered off and dried. Purification by chromatography, eluting withhexane/ethyl acetate gave 2-trifluoromethoxy-5-nitroaniline (9.8 g) as ayellow solid, m.p. 90°-91° C.

REFERENCE EXAMPLE 28

[0475] 2-Trifluoromethoxyacetanilide (31.6 g) was added to stirredconcentrated sulphuric acid at −10° C. A mixture of concentrated nitricacid and concentrated sulphuric acid was added maintaining at −5° C. to−10° C. The mixture was stirred at 0° C. for four hours and poured ontoexcess ice. The filtered solid was dissolved in dichloromethane, washedwith water, dried (magnesium sulphate) and evaporated to yield aresidue. This was purified by chromatography eluting with hexane/ethylacetate to give 5-nitro-2-trifluoromethoxyacetanilide (21.57 g), m.p.129°-130° C.

REFERENCE EXAMPLE 29

[0476] Acetyl chloride (66 ml) was added to a stirred solution of2-trifluoromethoxyaniline (150 g) and triethylamine in drydichloromethane (maintaining a temperature below 20° C.). After 3 hoursadditional stirring at 20° C. the mixture was washed with dilutehydrochloric acid, sodium carbonate solution and water, dried (magnesiumsulphate) and evaporated to dryness. The residue was recrystallised fromtoluene to furnish 2-trifluoromethoxyacetanilide (113.4 g), m.p.64°-66.5° C.

REFERENCE EXAMPLE 30

[0477] 6,7-Difluoroisatin (22.2 g) was added to a solution of sodiumhydroxide (2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was added at 40°C. or less over 20 minutes. After 1 hour the mixture was heated to 65°C. for 0.5 hours, cooled, poured onto water and acidified withconcentrated hydrochloric acid. The resulting solid was filtered, washedwith water and recrystallised from ethyl acetate/cyclohexane to give2-amino-3,4-difluorobenzoic acid (I 1.3 g) as an orange solid, m.p.207°-208° C.

REFERENCE EXAMPLE 31

[0478] 2,3-Difluoro-α-isonitrosoacetanilide (36.8 g) was added during 1hour to a stirred solution of concentrated sulphuric acid and water at65°-75° C. After an additional 20 minutes-at 80° C., the cooled mixturewas poured onto excess ice-water. Extraction with ethyl acetate wasfollowed by water washing, drying (magnesium sulphate) and evaporationto dryness to give a brown solid. Trituration with boiling cyclohexanegave after cooling, 6,7-difluoroisatin (22.2 g), m.p. 164.5°-167° C. asa brown solid.

REFERENCE EXAMPLE 32

[0479] Chloral hydrate (38.9 g) was added to a stirred solution ofsodium sulphate (219 g) in water. A solution of 2,3-difluoroaniline (25g) in a mixture of concentrated hydrochloric acid (19.4 ml) and water(117 ml) was added. A solution of hydroxylamine hydrochloride (41.35 g)in water was then added over 35 minutes and the mixture stirred for 1hour at 95°-100° C. After cooling the solid was filtered, washed withwater, then with petroleum ether and dried in a desiccator to furnish2,3-difluoro-α-isonitrosoacetanilide (36.8 g), m.p. 124.5°-125° C.

REFERENCE EXAMPLE 33

[0480] A solution of sodium hydroxide (2.38 g) in water was added to amixture of methyl 2-(N-methylsulphonyl)amino-4-trifluoromethoxybenzoateand methyl 2-[N,N-bis( methylsulphonyl)amino] trifluoromethoxybenzoate(8.26 g) in methanol at 15°-20° C. After an additional 15 minutes thesolid was filtered, dissolved in ethyl acetate, dried (magnesiumsulphate) and evaporated in vacuo to give methyl2-(N-methylsulphonyl)amino4-trifluoromethoxybenzoate as a brown solid(4.15 g) after trituration with hexane, NMR (CDCl₃) 3.0(s,3H),3.9(s,3H), 6.9(m,1H), 7.55(m,1H), 8.05(d,1H), 10.5(brs, 1H),

[0481] By proceeding in a similar manner methyl5-chloro-2-(N-methylsulphonyl)aminobenzoate was prepared m.p. 117°-120°C.

REFERENCE EXAMPLE 34

[0482] Methyl 2-nitro4-trifluoromethoxybenzoate (10 g) and 5% palladiumon activated carbon (0.5 g) in methanol was hydrogenated for 20 hours atambient temperature. The mixture was filtered and the filtrateevaporated to give methyl 2-amino4-trifluoromethoxybenzoate (8.35 g) asa brown oil, NMR (CDCl₃) 3.9(s,3H), 5.9(brs,2H), 6.55(m,2H), 7.9(d,1H),

REFERENCE EXAMPLE 35

[0483] 2-Nitro4-trifluoromethoxybenzoic acid (4.7 g) was heated underreflux conditions for 2 hours with oxalyl chloride (1.95 ml) and1,2-dichloroethane (25 ml) containing N,N-dimethylformamide (2 drops).The solvents were evaporated to dryness, the residue dissolved in drydichloromethane and added to a solution of triethylamine (2.08 g) in drymethanol. After 2 days, the solvent was evaporated and the residuepartitioned between dichloromethane and sodium bicarbonate solution. Theorganic phase was dried (magnesium sulphate), evaporated and the residuepurified by chromatography eluting with dichloromethane/hexane to givemethyl 2-nitrotrifluoromethoxybenzoate (4.9 g) as a yellow liquid, NMR(CDCl₃) 3.9(s,3H), 7.5(m,1H), 7.75(brs, 1H), 7.85(d,1H),

REFERENCE EXAMPLE 36

[0484] A mixture of 2-nitro4-trifluoromethoxybenzonitrile (8.7 g) and a55% sulphuric acid solution (46 ml) was heated under reflux conditionsfor 2 hours, the mixture poured onto ice and extracted with ether. Theether extracts were washed with water and back-extracted with sodiumhydroxide solution. Re-acidification of this aqueous extract andsubsequent extraction with ether gave a solution which was dried(magnesium sulphate) and evaporated to yield 2-nitro4-trifluoromethoxybenzoic acid (8.5 g) as a cream solid. NMR (d₆ DMSO)3.3(brs,1H), 7.8(m,1H), 8.05(d,1H), 8.15(m,1H),

REFERENCE EXAMPLE 37

[0485] A solution of 2-nitro-4-trifluoromethoxy-bromobenzene (2.0 g) inN,N-dimethylformamide (2 ml) was treated with copper (I) cyanide (0.62g) and the mixture heated at 150° C. for 1 hour. Toluene (10 ml) wasadded and the mixture was maintained at reflux for 1 hour. The mixturewas filtered and the filtrate evaporated to give a dark oil which waspurified by chromatography eluting with ethyl acetate/hexane (1:9) togive 2-nitro4-trifluoromethoxybenzonitrile (1.1 g) as a yellow liquid,NMR (CDCl₃) 7.65(m,1H), 8.0(d,1H), 8.15(m,1H),

REFERENCE EXAMPLE 38

[0486] Sodium hydride (4.6 g) in dry dioxan was stirred whilst addingN-methylmethanesulphonamide (6.4 g). When the effervescence hadsubsided, 2-chloro4,5-difluorobenzoic acid (10.0 g) was addedportionwise, followed by copper (I) chloride (1.7 g) and the mixtureheated under reflux conditions overnight. After evaporation to dryness,hydrochloric acid (2N, 100 ml) was added and the ire extracted withdichloromethane. The extract was dried (magnesium sulphate) andevaporated to dryness. The residue was dissolved in acetone, filteredand the filtrate evaporated and triturated with ether to give4,5-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid,m.p.159°-160.5° C.

[0487] By proceeding in a similar manner the following compounds wereprepared:

[0488] 4-iodo-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.174°-175° C. from 2-chloro-4-iodobenzoic acid;

[0489] 4-chloro-2-(N-methylsulphonylamino)benzoic acid, m.p. 188°-192°C. from 2-bromo4-chlorobenzoic acid, employing copper (I) bromide andmethanesulphonamide and 3 equivalents of sodium hydride;

[0490] 4-chloro-2-( N-methyl-N-isopropylsulphonyl)aminobenzoic acid,m.p. 178°-180° C., from 2-bromo 4-chlorobenzoic acid with copper (I)bromide and N-methyl-isopropylsulphonamide;

[0491] 4-chloro-2-(N -methoxy-N-methylsulphonyl)aminobenzoic acid, m.p.159°-160° C., from 2-bromo4-chlorobenzoic acid employing copper (I)bromide and N-methoxy-methanesulphonamide.

REFERENCE EXAMPLE 39

[0492] Thionyl chloride (21 ml) was added to methanol at 10° C. and thesolution stirred for 0.5 hours before being added to4-chloro-2-(methylsulphonylamino)benzoic acid (11.1 g). The mixture washeated under reflux conditions for 2 days after which time a furtheraddition of thionyl chloride (6ml) was made and reflux resumed for afurther 2 days. The solvent was evaporated to dryness, water added andthe mixture extracted with ethyl acetate. The extract was washed withsodium hydroxide solution (2N) then with water, dried (magnesiumsulphate) and evaporated to dryness to give methyl4-chloro-2-(methylsulphonylamino)benzoate (3.85 g) as a cream solid, NMR(CDCl₃) 3.25(s,3H), 3.9(s,3H), 73(dd,1H), 7.6(m,1H), 7.95(d,1H),10.2(brs,1H),

REFERENCE EXAMPLE 40

[0493] A solution of the magnesium salt of t-butyl 3-cyclopropyl3-oxopropanoate (1.85 g) in dry toluene was treated with a solution of4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoyl chloride (3.19 g) intoluene (10 ml). After stirring overnight at ambient temperature,trifluoroacetic acid (1.6 ml) was added and the mixture stirred for 2hours. The solution was washed (water), dried (magnesium sulphate),evaporated to dryness and the residue purified by chromatography elutingwith dichloromethane. This gave1-[4-chloro-2-(N-methyl-N-phenylsulphonyl)-amino]phenyl-3-cyclopropylpropan-1,3-dione(1.6 g) as an orange oil, NMR (CDCl₃) 1.0(m,2H), 1.25(m,2H), 2.15(m,1H),3.1(s,3H), 5.25(s,2H), 6.4(dd,1H), 7.15-7.7(m,7H) (keto form).

[0494] By proceeding in a similar manner the following compounds wereprepared:

[0495]1-[4-chloro-2-(N-benzylsulphonyl-N-methyl)amino]phenyl-3-cyclopropylpropan-1,3-dioneas an orange gum, NMR (CDCl₃) 1.0(m,2H), 1.2(m,2H), 1.8(m,1H),3.2(s,3H), 4.4(s,2H), 4.4(s,2H), 6.15(s,1H), 6.85(dd,1H), 7.45(m,7H),16.0(brs,1H), enol form.

[0496]1[4-chloro-2-(N-methyl-N-isopropylsulphonyl)amino]phenyl-3-cyclopropylpropan-1,3-dioneas an orange oil;

[0497] 1-[4-chloro-2-(N-methoxy-N-methylsulphonyl)amino]phenyl-3-cyclopropylpropan-1,3-dione,m.p. 84°-88° C.;

[0498]1-[4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione,NMR (CDCl₃) 0.9(broad m,6H), 1.05(m,2H), 1.25(m,2H), 1.8(m,1H),2.1(broad m,1H), 3.05(s,3H), 3.38(broad m,2H), 6.1(s,1H), 7.32(m,2H),16.1(brs,1H), enol form;

[0499]1-cyclopropyl-3-[3,4difluoro-2-(N-methyl-N-methylsulphonyl)amino]phenylpropan-1,3-dioneas an orange oil.

REFERENCE EXAMPLE 41

[0500] Magnesium (3.0 g) was stirred in methanol, carbon tetrachloride(0.5ml) added and the mixture warmed at 50° C. until the metal haddissolved (1.5 hours). Tert-butyl 3-cyclopropyl-3-oxopropanoate (20.0 g)was then added dropwise and the mixture heated under reflux conditionsfor 1 hour. The solvent was evaporated and re-evaporated after additionof toluene to give tert-butyl 3-cyclopropyl-3-oxopropanoate magnesiumsalt (29.9 g) as a white solid, m.p.>300° C., IR max (C=O) 1520, 1540;(C-O) 1350 cm.

[0501] According to a feature of the present invention, there isprovided a method for controlling the growth of weeds (i.e. undesiredvegetation) at a locus which comprises applying to the locus aherbicidally effective amount of at least one isoxazole derivative offormula (I). For this purpose, the isoxazole derivatives are normallyused in the form of herbicidal compositions (i.e. in association withcompatible diluents or carriers and/or surface active agents suitablefor use in herbicidal compositions), for example as hereinafterdescribed.

[0502] The compounds of formula (I) show herbicidal activity againstdicotyledonous (i.e. broad-leafed) and monocotyledonous (i.e. grass)weeds by pre- and/or post-emergence application. By the term“pre-emergence application” is meant application to the soil in whichthe weed seeds or seedlings are present before emergence of the weedsabove the surface of the soil. By the term “post-emergence application”is meant application to the aerial or exposed portions of the weedswhich have emerged above the surface of the soil. For example, thecompounds of formula (I) may be used to control the growth of:

[0503] broad-leafed weeds, for example, Abutilon theophrasti, Amaranthusretroflexus, Bidens pilosa, Chenopodium album, Galium aparine, Ipomoeaspp. e.g. Ipomoea purpurea, Sesbania exaltata, Sinapis arvensis, Solanumnigrum and Xanthium strumarium, and

[0504] grass weeds, for example Alopecurus myosuroides, Avena fatua,Digitaria sanguinalis, Echinochloa crus-galli, Sorghum bicolor, Eleusineindica and Setaria spp, e.g. Setaria faberii or Setaria viridis, and

[0505] sedges, for example, Cyperus esculentus.

[0506] The amounts of compounds of formula (I) applied vary with thenature of the weeds, the compositions used, the time of application, theclimatic and edaphic conditions and (when used to control the growth ofweeds in crop-growing areas) the nature of the crops. When applied to acrop-growing area, the rate of application should be sufficient tocontrol the growth of weeds without causing substantial permanent damageto the crop. In general, taking these factors into account, applicationrates between 0.01 kg and 5 kg of active material per hectare give goodresults. However, it is to be understood that higher or lowerapplication rates may be used, depending upon the particular problem ofweed control encountered.

[0507] The compounds of formula (I) may be used to control selectivelythe growth of weeds, for example to control the growth of those specieshereinbefore mentioned, by pre- or post-emergence application in adirectional or non-directional fashion, e.g. by directional ornon-directional spraying, to a locus of weed infestation which is anarea used, or to be used, for growing crops, for example cereals, e.g.wheat, barley, oats, maize and rice, soya beans, field and dwarf beans,peas, lucerne, cotton, peanuts, flax, onions, carrots, cabbage, oilseedrape, sunflower, sugar beet, and permanent or sown grassland before orafter sowing of the crop or before or after emergence of the crop. Forthe selective control of weeds at a locus of weed infestation which isan area used, or to be used, for growing of crops, e.g. the cropshereinbefore mentioned, application rates between 0.01 kg and 4.0 kg,and preferably between 0.01 kg and 2.0 kg, of active material perhectare are particularly suitable.

[0508] The compounds of formula (I) may also be used to control thegrowth of weeds, especially those indicated above, by pre- orpost-emergence application in established orchards and othertree-growing areas, for example forests, woods and parks, andplantations, e.g. sugar cane, oil palm and rubber plantations. For thispurpose they may be applied in a directional or non-directional fashion(e.g. by directional or non-directional spraying) to the weeds or to thesoil in which they are expected to appear, before or after planting ofthe trees or plantations at application rates between 0.25 kg and 5.0kg, and preferably between 0.5 kg and 4.0 kg of active material perhectare.

[0509] The compounds of formula (I) may also be used to control thegrowth of weeds, especially those indicated above, at loci which are notcrop-growing areas but in which the control of weeds is neverthelessdesirable.

[0510] Examples of such non-crop-growing areas include airfields,industrial sites, railways, roadside verges, the verges of rivers,irrigation and other waterways, scrublands and fallow or uncultivatedland, in particular where it is desired to control the growth of weedsin order to reduce fire risks. When used for such purposes in which atotal herbicidal effect is frequently desired, the active compounds arenormally applied at dosage rates higher than those used in crop-growingareas as hereinbefore described. The precise dosage will depend upon thenature of the vegetation treated and the effect sought.

[0511] Pre- or post-emergence application, and preferably pre-emergenceapplication, in a directional or non-directional fashion (e.g. bydirectional or non-directional spraying) at application rates between1.0 kg and 20.0 kg, and preferably between 5.0 and 10.0 kg, of activematerial per hectare are particularly suitable for this purpose.

[0512] When used to control the growth of weeds by pre-emergenceapplication, the compounds of formula (I) may be incorporated into thesoil in which the weeds are expected to emerge. It will be appreciatedthat when the compounds of formula (I) are used to control the growth ofweeds by post-emergence application, i.e. by application to the aerialor exposed portions of emerged weeds, the compounds of formula (1) willalso normally come into contact with the soil and may also then exercisea pre-emergence control on later-germinating weeds in the soil.

[0513] Where especially prolonged weed control is required, theapplication of the compounds of formula (I) may be repeated if required.

[0514] According to a further feature of the present invention, thereare provided compositions suitable for herbicidal use comprising one ormore of the isoxazole derivatives of formula (I), in association with,and preferably homogeneously dispersed in, one or more compatibleagriculturally-acceptable diluents or carriers and/or surface activeagents [i.e. diluents or carriers and/or surface active agents of thetype generally accepted in the art as being suitable for use inherbicidal compositions and which are compatible with compounds offormula (I)]. The term “homogeneously dispersed” is used to includecompositions in which the compounds of formula (I) are dissolved inother components. The term “herbicidal compositions” is used in a broadsense to include not only compositions which are ready for use asherbicides but also concentrates which must be diluted before use.Preferably, the compositions contain from 0.05 to 90% by weight of oneor more compounds of formula (I).

[0515] The herbicidal compositions may contain both a diluent or carrierand surface-active (e.g. wetting, dispersing, or emulsifying) agent.Surface-active agents which may be present in herbicidal compositions ofthe present invention may be of the ionic or non-ionic types, forexample sulphoricinoleates, quaternary ammonium derivatives, productsbased on condensates of ethylene oxide with allyl and polyaryl phenols,e.g. nonyl- or octyl-phenols, or carboxylic acid esters ofanhydrosorbitols which have been rendered soluble by etherification ofthe free hydroxy groups by condensation with ethylene oxide, alkali andalkaline earth metal salts of sulphuric acid esters and sulphonic acidssuch as dinonyl- and dioctyl-sodium sulphonosuccinates and alkali andalkaline earth metal salts of high molecular weight sulphonic acidderivatives such as sodium and calcium lignosulphonates and sodium andcalcium alkylbenzene sulphonates.

[0516] Suitably, the herbicidal compositions according to the presentinvention may comprise up to 10% by weight, e.g. from 0.05% to 10% byweight, of surface-active agent but, if desired, herbicidal compositionsaccording to the present invention may comprise higher proportions ofsurface-active agent, for example up to 15% by weight in liquidemulsifiable suspension concentrates and up to 25% by weight in liquidwater soluble concentrates.

[0517] Examples of suitable solid diluents or carriers are aluminiumsilicate, talc, calcined magnesia, kieselguhr, tricalcium phosphate,powdered cork, absorbent carbon black and clays such as kaolin andbentonite. The solid compositions (which may take the form of dusts,granules or wettable powders) are preferably prepared by grinding thecompounds of formula (I) with solid diluents or by impregnating thesolid diluents or carriers with solutions of the compounds of formula(I) in volatile solvents, evaporating the solvents and, if necessary,grinding the products so as to obtain powders. Granular formulations maybe prepared by absorbing the compounds of formula (I) (dissolved insuitable solvents, which may, if desired, be volatile) onto the soliddiluents or carriers in granular form and, if desired, evaporating thesolvents, or by granulating compositions in powder form obtained asdescribed above. Solid herbicidal compositions, particularly wettablepowders and granules, may contain wetting or dispersing agents (forexample of the types described above), which may also, when solid, serveas diluents or carriers.

[0518] Liquid compositions according to the invention may take the formof aqueous, organic or aqueous-organic solutions, suspensions andemulsions which may incorporate a surface-active agent. Suitable liquiddiluents for incorporation in the liquid compositions include water,glycols, tetrahydrofurfuryl alcohol, acetophenone, cyclohexanone,isophorone, toluene, xylene, mineral, animal and vegetable oils andlight aromatic and naphthenic fractions of petroleum (and mixtures ofthese diluents). Surface-active agents, which may be present in theliquid compositions, may be ionic or non-ionic (for example of the typesdescribed above) and may, when liquid, also serve as diluents orcarriers.

[0519] Powders, dispersible granules and liquid compositions in the formof concentrates may be diluted with water or other suitable diluents,for example mineral or vegetable oils, particularly in the case ofliquid concentrates in which the diluent or carrier is an oil, to givecompositions ready for use.

[0520] When desired, liquid compositions of the compound of formula (I)may be used in the form of self-emulsifying concentrates containing theactive substances dissolved in the emulsifying agents or in solventscontaining emulsifying agents compatible with the active substances, thesimple addition of water to such concentrates producing compositionsready for use.

[0521] Liquid concentrates in which the diluent or carrier is an oil maybe used without further dilution using the electrostatic spraytechnique.

[0522] Herbicidal compositions according to the present invention mayalso contain, if desired, conventional adjuvants such as adhesives,protective colloids, thickeners, penetrating agents, stabilisers,sequestering agents, anti-caking agents, colouring agents and corrosioninhibitors. These adjuvants may also serve as carriers or diluents.

[0523] Unless otherwise specified, the following percentages are byweight. Preferred herbicidal compositions according to the presentinvention are

[0524] aqueous suspension concentrates which comprise from 10 to 70% ofone or more compounds of formula (I), from 2 to 10% of surface-activeagent, from 0.1 to 5% of thickener and from 15 to 87.9% of water;

[0525] wettable powders which comprise from 10 to 90% of one or morecompounds of formula (I), from 2 to 10% of surface-active agent and from8 to 88% of solid diluent or carrier;

[0526] water soluble or water dispersible powders which comprise from 10to 90% of one or more compounds of formula,(I), from 2 to 40% of sodiumcarbonate and from 0 to 88%G of solid diluent;

[0527] liquid water soluble concentrates which comprise from 5 to 50%,e.g. 10 to 30%, of one or more compounds of formula (I), from 5 to 25%of surface-active agent and from 25 to 90%, e.g. 45 to 85%, of watermiscible solvent, e.g. dimethylformamide, or a mixture of water-misciblesolvent and water;

[0528] liquid emulsifiable suspension concentrates which comprise from10 to 70% of one or more compounds of formula (I), from 5 to 15% ofsurface-active agent, from 0.1 to 5% of thickener and from 10 to 84.9%of organic solvent;

[0529] granules which comprise from 1 to 90%, e.g. 2 to 10% of one ormore compounds of formula (I), from 0.5 to 7%, e.g. 0.5 to 2%, ofsurface-active agent and from 3 to 98.5%, e.g. 88 to 97.5%, of granularcarrier and

[0530] emulsifiable concentrates which comprise 0.05 to 90%, andpreferably from 1 to 60% of one or more compounds of formula (I), from0.01 to 10%, and preferably from 1 to 10%, of surface-active agent andfrom 9.99 to 99.94%, and preferably from 39 to 98.99%, of organicsolvent.

[0531] Herbicidal compositions according to the present invention mayalso comprise the compounds of formula (I) in association with, andpreferably homogeneously dispersed in, one or more other pesticidallyactive compounds and, if desired, one or more compatible pesticidallyacceptable diluents or carriers, surface-active agents and conventionaladjuvants as hereinbefore described. Examples of other pesticidallyactive compounds which may be included in, or used in conjunction with,the herbicidal compositions of the present invention include herbicides,for example to increase the range of weed species controlled for examplealachlor [2-chloro-2,6′-diethyl-N-(methoxy-methyl)-acetanilide],atrazine [2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine],bromoxynil [3,5-dibromo-4-hydroxybenzonitrile], chlortoluron[N′-(3-chloro-4-methylphenyl)-N,N-dimethylurea], cyanazine[2-chloro-4-(1-cyano-1- methylethylamino)-6-ethylamino-1,3,5-triazine],2,4-D [2,4-dichlorophenoxy-acetic acid], dicamba[3,6-dichloro-2-methoxybenzoic acid], difenzoquat [1,2-dimethyl-3,5-diphenyl-pyrazolium salts], flampropmethyl [methyl N-2-(N-benzoyl-3-chloro4-fluoroanilino)-propionate], fluometuron[N′-(3-trifluoro-methylphenyl)-N,N-dimethylurea], isoproturon[N′-(4-isopropylphenyl)-N,N-dimethylurea], insecticides, e.g. syntheticpyrethroids, e.g. permethrin and cypermethrin, and fungicides, e.g.carbamates, e.g. methylN-(1-butyl-carbamoyl-benzimidazol-2-yl)carbamate, and triazoles e.g.1-(4-chloro-phenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one.

[0532] Pesticidally active compounds and other biologically activematerials which may be included in, or used in conjunction with, theherbicidal compositions of the present invention, for example thosehereinbefore mentioned, and which are acids, may, if desired, beutilized in the form of conventional derivatives, for example alkalimetal and amine salts and esters.

[0533] According to a further feature of the present invention there isprovided an article of manufacture comprising at least one of theisoxazole derivatives of formula (I) or, as is preferred, a herbicidalcomposition as hereinbefore described, and preferably a herbicidalconcentrate which must be diluted before use, comprising at least one ofthe isoxazole derivatives of formula (I) within a container for theaforesaid derivative or derivatives of formula (I), or a said herbicidalcomposition, and instructions physically associated with the aforesaidcontainer setting out the manner in which the aforesaid derivative orderivatives of formula (1) or herbicidal composition contained thereinis to be used to control the growth of weeds. The containers willnormally be of the types conventionally used for the storage of chemicalsubstances which are solid at normal ambient temperatures and herbicidalcompositions particularly in the form of concentrates, for example cansand drums of metal, which may be internally lacquered, and plasticsmaterials, bottles or glass and plastics materials and, when thecontents of the container is a solid, for example granular, herbicidalcompositions, boxes, for example of cardboard, plastics materials andmetal, or sacks. The containers will normally be of sufficient capacityto contain amounts of the isoxazole derivative or herbicidalcompositions sufficient to treat at least one acre of ground to controlthe growth of weeds therein but will not exceed a size which isconvenient for conventional methods of handling. The instructions willbe physically associated with the container, for example by beingprinted directly thereon or on a label or tag affixed thereto. Thedirections will normally indicate that the contents of the container,after dilution if necessary, are to be applied to control the growth ofweeds at rates of application between 0.01 kg and 20 kg of activematerial per hectare in the manner and for the purposes hereinbeforedescribed.

[0534] The following Examples illustrate herbicidal compositionsaccording to the present invention:

EXAMPLE C1

[0535] A soluble concentrate is formed from: Active ingredient(compound 1) 20% w/v Potassium hydroxide solution 33% w/v 10% v/vTetrahydrofurfuryl alcohol (THFA) 10% v/v Water to 100 volumes.

[0536] by stirring THFA, active ingredient (compound 1 +L) and 90%volume of water and slowly adding the potassium hydroxide solution untila steady pH 7-8 is obtained then making up to volume with water.

[0537] Similar soluble concentrates may be prepared as described aboveby replacing the isoxazole (compound 1) with other compounds of formula(I).

EXAMPLE C2

[0538] A wettable powder is formed from: Active ingredient (compound 1)50% w/w Sodium dodecylbenzene sulphonate  3% w/w Sodium lignosulphate 5% w/w Sodium formaldehyde alkylnaphthalene sulphonate  2% w/wMicrofine silicon dioxide  3% w/w and China clay 37% w/w

[0539] by blending the above ingredients together and grinding themixture in an air jet mill.

[0540] Similar wettable powders may be prepared as described above byreplacing the isoxazole (compound 1) with other compounds of formula(I).

EXAMPLE C3

[0541] A water soluble powder is formed from: Active ingredient(compound 1) 50% w/w Sodium dodecylbenzenesulphonate  1% w/w Microfinesilicon dioxide  2% w/w Sodium bicarbonate 47% w/w

[0542] by mixing the above ingredients and grinding the above mixture ina hammer mill.

[0543] Similar water soluble powders may be prepared as described aboveby replacing the isoxazole (compound 1) with other compounds of formula(I).

[0544] The compounds of the invention have been used in herbicidalapplications according to the following procedures.

[0545] METHOD OF USE OF HERBICIDAL COMPOUNDS:

[0546] a) General

[0547] Appropriate quantities of the compounds used to treat the plantswere dissolved in acetone to give solutions equivalent to applicationrates of up to 4000 g test compound per hectare (g/ha). These solutionswere applied from a standard laboratory herbicide sprayer delivering theequivalent of 290 liters of spray fluid per hectare.

[0548] b) Weed control: Pre-emergence

[0549] The seeds were sown in 70 mm square, 75 mm deep plastic pots innon-sterile soil. The quantities of seed per pot were as follows:—Approx number of seeds/pot Weed species 1) Broad-leafed weeds Abutilontheophrasti 10 Amaranthus retroflexus 20 Galium aparine 10 Ipomoeapurpurea 10 Sinapis arvensis 15 Xanthium strumarium 2 2) Grass weedsAlopecurus myosuroides 15 Avena fatua 10 Echinochloa crus-galli 15Setaria viridis 20 3) Sedges Cyperus esculentus 3 Crop 1) Broad-leafedCotton 3 Soya 3 2) Grass Maize 2 Rice 6 Wheat 6

[0550] The compounds of the invention were applied to the soil surface,containing the seeds, as described in (a). A single pot of each crop andeach weed was allocated to each treatment, with unsprayed controls andcontrols sprayed with acetone alone.

[0551] After treatment the pots were placed on capillary matting kept ina glass house, and watered overhead. Visual assessment of crop damagewas made 20-24 days after spraying. The results were expressed as thepercentage reduction in growth or damage to the crop or weeds, incomparison with the plants in the control pots.

[0552] c) Weed control: Post-emergence

[0553] The weeds and crops were sown directly into John Innes pottingcompost in 75 mm deep, 70 mm square pots except for Amaranthus which waspricked out at the seedling stage and transferred to the pots one weekbefore spraying. The plants were then grown in the greenhouse untilready for spraying with the compounds used to treat the plants. Thenumber of plants per pot were as follows:— Number of plants per potGrowth stage 1) Broad leafed weeds Weed species Abutilon theophrasti 31-2 leaves Amaranthus retroflexus 4 1-2 leaves Galium aparine 3 1^(st)whorl Ipomoea purpurea 3 1-2 leaves Sinapis arvensis 4 2 leaves Xanthiumstrumarium 1 2-3 leaves 2) Grass weeds Weed species Alopecurusmyosuroides  8-12 1-2 leaves Avena fatua 12-18 1-2 leaves Echinochloacrus-galli 4 2-3 leaves Setaria viridis 15-25 1-2 leaves. 3) Sedges Weedspecies Cyperus esculentus 3 3 leaves. 1) Broad leafed Crops Cotton 2 1leaf Soya 2 2 leaves. 2) Grass Crops Maize 2 2-3 leaves Rice 4 2-3leaves Wheat 5 2-3 leaves.

[0554] The compounds used to treat the plants were applied to the plantsas described in (a). A single pot of each crop and weed species wasallocated to each treatment, with unsprayed controls and controlssprayed with acetone alone.

[0555] After treatment the pots were placed on capillary matting in aglass house, and watered overhead once after 24 hours and then bycontrolled sub-irrigation. Visual assessment of crop damage and weedcontrol was made 20-24 days after spraying. The results were expressedas the percentage reduction in growth or damage to the crop or weeds, incomparison with the plants in the control pots.

[0556] The compounds of the invention, used at 4 kg/ha or less, haveshown an excellent level of herbicidal activity together with croptolerance on the weeds used in the foregoing experiments.

[0557] When applied pre- or post-emergence at 1000 g/ha compounds 1 to34 gave at least 90% reduction in growth of one or more of the weedspecies.

1. A 4-benzoylisoxazole derivative of formula (I):

wherein: R represents the hydrogen atom or a group —CO₂R⁴; R¹represents:— a straight- or branched-chain alkyl group containing up tosix carbon atoms which is optionally substituted by one or more halogenatoms; or a cycloalkyl group containing from three to six carbon atomsoptionally substituted by one or more R⁵ groups or one or more halogenatoms; R² represents:— a halogen atom; a straight- or branched-chainalkyl alkenyl or alkynyl group containing up to six carbon atomsoptionally substituted by one or more halogen atoms; a straight- orbranched-chain alkyl group containing up to six carbon atoms which issubstituted by one or more groups —OR⁵; a group selected from nitro,cyano, —CO₂R⁵, —S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵, —COR⁵, —NR⁵R⁶,-N(R⁸)SO_(q)R⁷, —CONR⁹R¹⁰ and —OR⁵¹; phenyl optionally substituted byfrom one to three groups R²¹ which may be the same or different; R³represents —S(O)_(q)R⁷; X represents a group —N(R⁸)—; n represents zeroor an integer from one to four; where n is greater than one the groupsR² may be the same or different; R⁴ represents a straight- orbranched-chain alkyl group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms; R⁵, R⁵¹ and R⁶, which may bethe same or different, each represents:— the hydrogen atom; a straight-or branched-chain allyl, alkenyl or alkynyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms; phenyloptionally substituted by from one to five groups R² which may be thesame or different; or a cycloalkyl group containing from three to sixcarbon atoms; R⁷ represents:— a straight- or branched-chain alkyl,alkenyl or alkynyl group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms; a cycloalkyl group containingfrom three to six carbon atoms; phenyl or benzyl optionally substitutedby from one to five groups R²¹ which may be the same or different; or—NR⁹R¹⁰; R⁸ represents: the hydrogen atom; or a straight- orbranched-chain alkyl, alkenyl or alkynyl group containing up to tencarbon atoms optionally substituted by one or more halogen atoms; acycloalkyl group containing from three to six carbon atoms; phenyloptionally substituted by from one to five groups which may be the sameor different selected from halogen, nitro, cyano, R⁵, S(O)_(p)R⁵ and—OR⁵; or a group —OR¹¹; R⁹ represents:— the hydrogen atom; a straight-or branched-chain alkyl group containing up to six carbon atomsoptionally substituted by one or more halogen atoms; or phenyloptionally substituted by from one to five groups R² which may be thesame or different; R¹⁰ represents a group selected from R⁵ and —OR¹¹; orR⁹ and R¹⁰, together with the nitrogen to which they are attached, mayform a 5 or 6 membered ring optionally containing an oxygen or nitrogenatom in the ring, wherein the ring is optionally substituted by one ormore alkyl groups containing up to 3 carbon atoms; R¹¹ represents astraight- or branched-chain alkyl group containing up to six carbonatoms; R²¹ represents:— a halogen atom; a straight- or branched-chainalkyl group containing up to three carbon atoms optionally substitutedby one or more halogen atoms; or a group selected from nitro, cyano,—S(O)_(p)R⁵ and —OR⁵; m represents one, two or three; p represents zero,one or two; and q represents zero or two; or an agriculturallyacceptable salt thereof
 2. A compound according to claim 1 wherein: Rrepresents the hydrogen atom or a group —CO₂R⁴; R¹ represents:— astraight- or branched-chain alkyl group containing up to six carbonatoms which is optionally substituted by one or more halogen atoms; or acycloalkyl group containing from three to six carbon atoms optionallysubstituted by one or more R⁵ groups; R² represents:— a straight- orbranched-chain alkyl, alkenyl or alkynyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms; astraight- or branched-chain alkyl group containing up to six carbonatoms which is substituted by a group —OR⁵; a halogen atom; phenyloptionally substituted by from one to three groups R²¹ which may be thesame or different; a group selected from —COR⁵, nitro, cyano, —CO₂R⁵;—S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵, —N(R⁸)SO₂R⁷, —CONR⁹R¹⁰ and —OR⁵¹; R³represents —S(O)_(q)R⁷; X represents a group —N(R⁸)—; n represents zeroor an integer from one to four; where n is greater than one the groupsR² may be the same or different; R⁴ represents a straight- orbranched-chain alkyl group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms; R⁵ represents:— a straight- orbranched-chain alkyl, alkenyl or alkynyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms; or acycloalkyl group containing from three to six carbon atoms; R⁵¹represents:— a straight- or branched-chain alkyl, alkenyl or alkynylgroup containing up to six carbon atoms optionally substituted by one ormore halogen atoms; a cycloalkyl group containing from three to sixcarbon atoms; or phenyl optionally substituted by from one to fivegroups which may be the same or different elected from a halogen atom, astraight- or branched-chain alkyl group containing up to three carbonatoms optionally substituted by one or more halogen atoms; nitro, cyano,—S(O)_(p)R⁵ and —OR⁵; R⁶ represents:— a straight- or branched-chainalkyl, alkenyl or alkynyl group containing up to six carbon atomsoptionally substituted by one or more halogen atoms; a cycloalkyl groupcontaining from three to six carbon atoms; or phenyl optionallysubstituted by from one to five groups which may be the same ordifferent selected from a halogen atom, a straight- or branched-chainalkyl group containing up to three carbon atoms optionally substitutedby one or more halogen atoms; nitro, cyano, —S(O)_(p)R⁵ and —OR⁵; R⁷represents:— a straight- or branched-chain alkyl, alkenyl or alkynylgroup containing up to six carbon atoms optionally substituted by one ormore halogen atoms; a cycloalkyl group containing from three to sixcarbon atoms; phenyl optionally substituted by from one to five groupsR²¹ which may be the same or different; or —NR⁹R¹⁰; R⁸ represents: thehydrogen atom; or a straight- or branched-chain alkyl, alkenyl oralkynyl group containing up to six carbon atoms optionally substitutedby one or more halogen atoms; a cycloalkyl group containing from threeto six carbon atoms; phenyl optionally substituted by from one to fivegroups which may be the same or different selected from a halogen atom,a straight- or branched-chain alkyl group containing up to three carbonatoms optionally substituted by one or more halogen atoms; nitro, cyano,—S(O)_(p)R⁵ and —OR⁵; or a group —OR¹¹; R⁹ represents hydrogen or astraight- or branched-chain alkyl group containing up to six carbonatoms optionally substituted by one or more halogen atoms; R¹⁰represents a group selected from R⁵ and —OR¹¹; or R⁹ and R¹⁰, togetherwith the nitrogen to which they are attached, may form a 5 or 6 memberedring optionally containing an oxygen or nitrogen atom in the ring,wherein the ring is optionally substituted by one or more alkyl groupscontaining up to 3 carbon atoms; R¹¹ represents a straight- orbranched-chain alkyl group containing up to six carbon atoms; R²¹represents:— a halogen atom; a straight- or branched-chain alkyl groupcontaining up to three carbon atoms optionally substituted by one ormore halogen atoms; or a group selected from nitro, cyano, —S(O)_(p)R⁵and —OR⁵; m represents one, two or three; p represents zero, one or two;and q represents two.
 3. A compound according to claim 1 wherein: Rrepresents the hydrogen atom or a group —CO₂R⁴; R¹ represents:— astraight- or branched-chain alkyl group containing up to six carbonatoms which is optionally substituted by one or more halogen atoms; or acycloalkyl group containing from three to six carbon atoms optionallysubstituted by one or more R⁵ groups or one or more halogen atoms; R²represents:— a halogen atom; a straight- or branched-chain alkyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms; a straight- or branched-chain alkyl group containing upto six carbon atoms which is substituted by one or more groups —OR⁵; agroup selected from nitro, cyano, —CO₂R⁵, —S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵,—COR⁵, —NR⁵R⁶, —N(R⁸)SO_(q)R⁷ and —OR⁵¹; R³ represents —S(O)R⁷; Xrepresents a group —N(R⁸)— n represents zero or an integer from one tofour; where n is greater than one the groups R² may be the same ordifferent; R⁴ represents a straight- or branched-chain alkyl groupcontaining up to six carbon atoms which is optionally substituted by oneor more halogen atoms; R⁵, R⁵¹ and R⁶, which may be the same ordifferent, each represents: the hydrogen atom; a straight- orbranched-chain alkyl group containing up to six carbon atoms which isoptionally substituted by one or more halogen atoms; phenyl optionallysubstituted by from one to five groups R² which may be the same ordifferent; R⁷ represents: a straight- or branched-chain alkyl groupcontaining up to six carbon atoms which is optionally substituted by oneor more halogen atoms: phenyl optionally substituted by from one to fivegroups R²¹ which may be the same or different; or a group —NR⁹R¹⁰; R⁸represents: the hydrogen atom; a straight- or branched-chain alkyl,alkenyl or alkynyl group containing up to ten carbon atoms which isoptionally substituted by one or more halogen atoms; or phenyloptionally substituted from one to five groups which may be the same ordifferent selected from nitro, halogen, R⁵ and —OR⁵; R⁹ and R¹⁰, whichmay be the same or different, each represents:— the hydrogen atom; astraight- or branched-chain alkyl group containing up to six carbonatoms optionally substituted by one or more halogen atoms; or phenyloptionally substituted by from one to five groups R² which may be thesame or different; R²¹ represents:— a halogen atom; a straight- orbranched-chain alkyl group containing up to three carbon atomsoptionally substituted by one or more halogen atoms; or a group selectedfrom nitro, cyano, —S(O)_(p)R⁶ and —OR⁵; p represents zero, 1 or 2; qrepresents zero or 2; and m represents 1, 2 or
 3. 4. A compoundaccording to claim 1, 2 or 3 wherein the 5- and 6- positions of thebenzoyl ring are unsubstituted.
 5. A compound according to any one ofthe preceding claims wherein the 2-position of the benzoyl ring issubstituted.
 6. A compound according to any one of claims 1, 2, 4 and 5wherein: R¹ represents:— a straight- or branched-chain alkyl groupcontaining up to six carbon atoms which is optionally substituted by oneor more halogen atoms; or a cycloalkyl group containing from three tosix carbon atoms optionally substituted by one or more methyl groups; R²represents:— a halogen atom; a straight- or branched-chain alkyl,alkenyl or alkynyl group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms; a straight- or branched-chainalkyl group containing up to six carbon atoms which is substituted by agroup —OR⁵; phenyl optionally substituted by from one to three groupsR²¹ which may be the same or different; or a group selected from —COR⁵,cyano, nitro, —CO₂R⁵, —S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵, —N(R⁸)SO₂R⁷ and—OR⁵¹; n represents zero or an integer from one to three; where n isgreater than one the groups R² may be the same or different; R⁵represents:— a straight- or branched-chain alkyl group containing up tosix carbon atoms optionally substituted by one or more halogen atoms; ora cycloalkyl group containing from three to six carbon atoms; R⁵¹ andR⁶, which may be the same or different, each represents:— a straight- orbranched-chain alkyl or alkenyl group containing up to six carbon atomsoptionally substituted by one or more halogen atoms; a straight- orbranched-chain alkynyl group containing from three to six carbon atoms;a cycloalkyl group containing three to six carbon atoms; R⁷ represents:—a straight- or branched-chain alkyl or alkenyl group containing up tosix carbon atoms optionally substituted by one or more halogen atoms; astraight- or branched-chain alkynyl group containing from three to sixcarbon atoms; a cycloalkyl group containing three to six carbon atoms;or phenyl optionally substituted by from one to three groups R²¹ whichmay be the same or different; R⁸ represents:— the hydrogen atom; or astraight- or branched-chain alkyl or alkenyl group containing up to sixcarbon atoms optionally substituted by one or more halogen atoms; astraight- or branched-chain alkynyl group containing from three to sixcarbon atoms; or a cycloalkyl group containing three to six carbonatoms; R²¹ represents:— a halogen atom; a straight- or branched-chainalkyl group containing up to three carbon atoms optionally substitutedby one or more halogen atoms; or a group selected from nitro, cyano,—S(O)_(p)R⁵ and —OR⁵; q represents two; m represents two or three; and prepresents zero, one or two.
 7. A compound according to-any one ofclaims 1, 2 and 4 to 6 wherein: R¹ represents:— a straight- orbranched-chain alkyl group containing up to three carbon atoms; or acycloalkyl group containing three or four carbon atoms optionallysubstituted by a methyl group; R² represents:— a chlorine, bromine orfluorine atom; or a straight- or branched-chain alkyl, alkenyl oralkynyl group containing up to four carbon atoms optionally substitutedby one or more halogen atoms; a straight- or branched-chain alkyl groupcontaining up to four carbon atoms which is substituted by a group —OR⁵;or a group selected from —COR⁵, —CO₂R⁵, —S(O)_(p)R⁶, —O(CH₂)_(m)OR⁵,—N(R⁸)SO₂R⁷ and —OR⁵¹; R⁵ and R⁶, which may be the same or different,each represents:— a straight- or branched-chain alkyl group containingup to four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms; or a cyclopropyl group; R⁵¹ and R⁷, which maybe the same or different, each represents:— a straight- orbranched-chain alkyl or alkenyl group containing up to four carbon atomsoptionally substituted by one or more chlorine, bromine or fluorineatoms; a straight- or branched-chain alkynyl group containing three orfour carbon atoms; or a cyclopropyl group; R⁸ represents:— the hydrogenatom; a straight- or branched-chain alkyl or alkenyl group containing upto four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms; a straight- or branched-chain alkynyl groupcontaining three or four carbon atoms; or a cyclopropyl group; qrepresents two; m represents two or three; and p represents zero, one ortwo.
 8. A compound according to any one of claims 1, 2 and 4 to 7wherein: R¹ represents methyl, ethyl, isopropyl, cyclopropyl or1-methylcyclopropyl; R² represents:— a bromine, chlorine or fluorineatom; or a straight- or branched-chain allyl or alkenyl group containingup to four carbon atoms optionally substituted by one or more chlorine,bromine or fluorine atoms; a group selected from —COR⁵, —CO₂R⁵, —SR⁶,—O(CH₂)_(m)OR⁵, —OR⁵¹ and —N(R⁸)SO₂R⁷; or a straight- or branched chainalkyl group containing up to four carbon atoms which is substituted by—OR⁵; R⁵ and R⁶, which may be the same or different, each represents astraight- or branched-chain alkyl group containing up to three carbonatoms; R⁵¹ represents:— a straight- or branched-chain alkyl groupcontaining up to four carbon atoms optionally substituted by one or morechlorine, bromine or fluorine atoms; a straight- or branched-chainalkenyl or alkynyl group containing three or four carbon atoms; or acyclopropyl group; R⁷ represents:— a straight- or branched-chain allylgroup containing up to three carbon atoms optionally substituted by oneor more chlorine, bromine, or fluorine atoms; or I an allyl groupoptionally substituted by one or more chlorine, fluorine or bromineatoms; R⁸ represents:— the hydrogen atom; a straight- or branched-chainalkyl group containing up to three carbon atoms optionally substitutedby one or more chlorine, bromine, or fluorine atoms; or an allyl groupoptionally substituted by one or more chlorine, fluorine or bromineatoms; q represents two; and m represents two or three.
 9. A compoundaccording to claim 1 wherein R represents hydrogen or —CO₂Et; R¹represents cyclopropyl; R² represents a halogen atom or a group selectedfrom nitro, trifluoromethyl, methyl, trifluoromethoxy, —S(O)_(p)Me and—N(R⁸)SO₂R⁷; R⁷ represents a straight- or branched-chain allyl groupcontaining up to three carbon atoms, phenyl or benzyl; R⁸ represents astraight- or branched-chain alkyl group containing up to four carbonatoms, methoxy or phenyl; p is zero, one or two; n represents zero, oneor two; and q represents two.
 10. A compound according to any one of thepreceding claims wherein a group —XR3 is in the 2- or 4- position of thebenzoyl ring.
 11. A compound according to any one of the precedingclaims wherein: R¹ represents cyclopropyl; R² represents a halogen atom;R⁷ represents methyl; R⁸ represents hydrogen or methyl; and n representszero or one.
 12. The compound according to claim 1 which is:4-[2-chloro-4-(methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-methyl-N-methylphonyl)aminobenzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-benzoyl]isoxazole;4-[4-chloro-2-(N-ethyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-4-nitro-benzoyl]isoxazole;5-cyclopropyl-4-[4-(N-methyl-N-methylsulphonyl)amino-2-nitro-benzoyl]isoxazole;5-cyclopropyl-4-[4-methyl-2-(N-methyl-N-methylsulphonyl)amino-benzoyl]isoxazole;4-[4-chloro-2-(N-n-propyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonyl)amino-4-methylsulphonylbenzoyl]isoxazole;5-cyclopropyl-4-[3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoyl]isoxazole;5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole;5-cyclopropyl4-[2-(N-phenyl-N-methylsulphonyl)amino-benzoyl]isoxazole;4-[4-bromo-2-(N-methyl-4-methylsulphonyl)amino-benzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-4-methylsulphonylbenzoyl]isoxazole;ethyl5-cyclopropyl4-[4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoyl]isoxazole-3-carboxylate;4-[4-chloro-2-(N-methyl-N-ethylsulphonylamino)benzoyl]-5-cyclopropyl-isoxazole;5-cyclopropyl-4-[2,4bis(N-methyl-N-methylsulphonyl)-aminobenzoyl]isoxazole;5-cyclopropyl[2-(N-methyl-N-methylsulphonyl)amino4-fluorobenzoyl]isoxazole;-4-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[2-chloro-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cycopropylisoxazole;4-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino4-trifluoromethoxybenzoyl]isoxazole;4-[5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;5-cyclopropyl-4-[2-fluoro4(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;5-cyclopropyl-4-[3,4-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;5-cyclopropyl-4-[4,5-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;5-cyclopropyl4-[4-iodo-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]isoxazole;4-[4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-methyl-N-n-propylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-methyl-N-isopropylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;4-[4-chloro-2-(N-methoxy-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;or ethyl5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole-3-carboxylate.13. A process for the preparation of a compound of formula (I) asdefined in claim 1 which comprises: (a) where R represents hydrogenexcluding compounds of formula (I) in which a group —XR³ is in the orthoposition and X is —NH—, reacting a compound of formula (II):

wherein L is a leaving group and R¹, R², R³, a and X are as defined inclaim 1 provided that when X is —NH— the group —XR³ is not in the orthoposition of the phenyl ring, with hydroxylamine or a salt ofhydroxylamine; (b) where R represents hydrogen, reacting a compound offormula (m):

wherein R¹ is as defined in claim 1 and Y represents a carboxy group ora reactive derivative thereof or a cyano group, with an appropriateorganometallic reagent; (c) where R represents a group —CO₂R⁴ excludingcompounds of formula (I) in which a group —XR³ is in the ortho positionand X is —NH—, reacting a compound of formula (IV)

wherein R¹, R² ₁ R³, X and n are as defined in claim 1 provided thatwhen X is —NH— the group —XR³ is not in the ortho position of the phenylring, and P is a leaving group, with a compound of formula R⁴O₂CC(Z)=NOHwherein R⁴ is as defined in claim 1 and Z is a halogen atom; (d) where Rrepresents a group —CO₂R⁴ excluding compounds of formula (I) in which agroup —XR³ is in the ortho position and X is —NH—, reacting a compoundof formula (V):

wherein R¹, R², R³, X and n are as defined provided that when X is —NH—the group —XR³ is not in the ortho position of the phenyl ring, with acompound of formula R⁴O₂CC(Z)=NOH wherein R⁴ is as defined in claim 1and Z is a halogen atom; (e) where R represents a group —CO₂R⁴ excludingcompounds of formula (I) in which a group —XR³ is in the ortho positionand X is —NH—, reacting a salt of a compound of formula (VI):

wherein R¹, R², R³, X and n are as defined in claim 1 provided that whenX is —NH— the group —XR³ is not in the ortho position of the phenylring, with a compound of formula R⁴O₂CC(Z)=NOH wherein R⁴ is as definedin claim I and Z is a halogen atom; (f) where X represents —NH—,deprotecting a compound of formula (VII):

wherein R, R¹, R² and n are as defined in claim 1 and A represents—NX¹R³ wherein R³ is as defined in claim 1 and XI represents aprotecting group which can be removed under acidic or neutral reactionconditions (g) where p is one or two and/or q is the oxidation of thesulphur atom of the corresponding compound of formula (I) in which p is0 or 1 and/or q is zero; optionally followed by the conversion of thecompound of formula (I) thus obtained into an agriculturally acceptablesalt.
 14. A herbicidal composition which comprises as active ingredienta herbicidally effective amount of a 4-benzoylisoxazole derivative offormula (I) as defined in any one of claims 1 to 11 or an agriculturallyacceptable salt-thereof in association with an agriculturally acceptablediluent or carrier and/or surface active agent.
 15. A herbicidalcomposition according to claim 14 in the form of an aqueous suspensionconcentrate, a wettable powder, a water soluble or water dispersiblepowder, a liquid water soluble concentrate, a liquid emulsifiablesuspension concentrate, a granule or an emulsifiable concentrate.
 16. Amethod for controlling the growth of weeds at a locus which comprisesapplying to the locus a herbicidally effective amount of a4-benzoylisoxazole derivative of formula (I) as defined in any one ofclaims 1 to 11 or an agriculturally acceptable salt thereof.
 17. Amethod according to claim 16 in which the locus is an area used, or tobe used, for growing of crops and the compound is applied at anapplication rate from 0.01 kg to 4.0 kg per hectare.
 18. A compound offormula:

in which R, R¹, R² and n are-as defined in claim 1 and A represents—NX¹R³, wherein R³ is as defined in claim 1 and X¹ represents aprotecting group which can be removed under acidic or neutral reactionconditions.